Note: This page contains sample records for the topic normal t-cell development from Science.gov.
While these samples are representative of the content of Science.gov,
they are not comprehensive nor are they the most current set.
We encourage you to perform a real-time search of Science.gov
to obtain the most current and comprehensive results.
Last update: August 15, 2014.
1

Autoimmunity develops in lupus-prone NZB mice despite normal T cell tolerance.  

PubMed

NZB mice spontaneously develop an autoimmune disease characterized by production of anti-RBC, -lymphocyte, and -ssDNA Abs. Evidence suggests that the NZB mouse strain has all of the immunologic defects required to produce lupus nephritis but lacks an MHC locus that allows pathogenic anti-dsDNA Ab production. The capacity to produce diverse autoantibodies in these mice raises the possibility that they possess a generalized defect in self-tolerance. To determine whether this defect is found within the T cell subset, we backcrossed a transgene encoding bovine insulin (BI) onto the NZB background. In nonautoimmune BALB/c mice, the BI transgene induces a profound but incomplete state of T cell tolerance mediated predominantly by clonal anergy. Comparison of tolerance in NZB and BALB/c BI-transgenic mice clearly demonstrated that NZB T cells were at least as tolerant to BI as BALB/c T cells. NZB BI-transgenic mice did not spontaneously produce anti-BI Abs, and following antigenic challenge, BI-specific Ab production was comparably reduced in both BI-transgenic NZB and BALB/c mice. Further, in vitro BI-specific T cell proliferation and cytokine secretion were appropriately decreased for primed lymph node and splenic T cells derived from NZB BI-transgenic relative to their nontransgenic counterparts. These data indicate that a generalized T cell tolerance defect does not underlie the autoimmune disease in NZB mice. Instead, we propose that the T cell-dependent production of pathogenic IgG autoantibodies in these mice arises from abnormal activation of T cells in the setting of normal but incomplete tolerance. PMID:9794382

Wither, J; Vukusic, B

1998-11-01

2

Early ?? T cell development in the thymus of normal and genetically altered mice  

Microsoft Academic Search

The vast majority of T lymphocytes, with the exception of gut-associated, intraepithelial lymphocytes, differentiate and mature inside the thymus. Early T cell development is characterized by expansion and differentiation of thymocytes which do not yet express mature TCRs on their cell surface. Important events in early thymocyte development are controlled by a pre-TCR complex consisting of a conventional TCR? chain

Hans Jörg Fehling; Harald von Boehmer

1997-01-01

3

T Cells Development Is Different between Thymus from Normal and Intrauterine Growth Restricted Pig Fetus at Different Gestational Stage  

PubMed Central

This experiment was conducted to evaluate the development of T cells in intrauterine growth retarded (IUGR) piglets at different gestational stages, and tentatively explore the relationship between T cells development and the Notch signaling pathway. A total of 18 crossbred (Landrace×Large white) primiparous sows were mated at similar weights and estruses and euthanized at d 60, 90 and 110 of gestation with six replicates for each time point. One IUGR and one normal fetus were picked from each litter. The T-cell subsets, mRNA expression of Delta-like1, Delta-like4, Jagged1, and Notch2 genes in the thymus were investigated. Compared to normal piglets, CD3+CD4?CD8+ cells in IUGR fetuses at d 90 was 0.13% lower (p<0.05). At d 110 of gestation CD8+ T cells in IUGR fetuses was 0.19% lower (p<0.05). The percentage of CD8+ T cells was 3.14% lower (p<0.05) of the total T cells in IUGR pigs at d 60. The abundance of Notch2 and Delta-like4 mRNA at d 110 was 20.93% higher and 0.77% (p<0.05) lower, and Delta-like1 mRNA at d 90 was 0.19% (p<0.05) higher compared to normal pigs. These results suggested that normal fetuses had a greater proportion of T-cell subsets at earlier gestation periods, and the Notch signaling pathway was likely partially responsible for these differences to some degree.

Lin, Yan; Wang, Junjun; Wang, Xiaoqiu; Wu, Weizong; Lai, Changhua

2013-01-01

4

Elevated mitochondrial superoxide disrupts normal T-cell development to impair adaptive immune responses to an influenza challenge  

PubMed Central

Reactive oxygen species (ROS) are critical in a broad spectrum of cellular processes including signaling, tumor progression, and innate immunity. The essential nature of ROS signaling in the immune systems of Drosophila and zebrafish has been demonstrated; however, the role of ROS, if any, in mammalian adaptive immune system development and function remains unknown. The current work provides the first clear demonstration that thymus specific elevation of mitochondrial superoxide (O2·?) disrupts normal T-cell development to impair function of the mammalian adaptive immune system. To assess the effect of elevated mitochondrial superoxide in the developing thymus, we used a T-cell specific knockout of manganese superoxide dismutase (i.e. SOD2) and have thus established a murine model to examine the role of mitochondrial superoxide in T-cell development. Conditional loss of SOD2 led to increased superoxide, apoptosis, and developmental defects in the T-cell population resulting in immunodeficiency and susceptibility to influenza A virus (IAV), H1N1. This phenotype was rescued with mitochondrially targeted superoxide scavenging drugs. These new findings demonstrate that loss of regulated levels of mitochondrial superoxide lead to aberrant T-cell development and function, and further suggest that manipulations of mitochondrial superoxide levels may significantly alter clinical outcomes resulting from viral infection.

Case, Adam J.; McGill, Jodi L.; Tygrett, Lorraine T.; Shirasawa, Takuji; Spitz, Douglas R.; Waldschmidt, Thomas J.; Legge, Kevin L.; Domann, Frederick E.

2010-01-01

5

Gadd45  Is Dispensable for Normal Mouse Development and T-Cell Proliferation  

Microsoft Academic Search

Gadd45g, a family member of the growth arrest and DNA damage-inducible gene family 45 (Gadd45), is strongly induced by interleukin-2 (IL-2) in peripheral T cells. While in most tissues all Gadd45 family members are expressed, Gadd45g is the only member that is induced by IL-2. Here we show that the IL-2-induced expression of Gadd45g is dependent on a signaling pathway

ANGELIKA HOFFMEYER; ROLAND PIEKORZ; RICHARD MORIGGL; JAMES N. IHLE

2001-01-01

6

Pax1 is expressed during development of the thymus epithelium and is required for normal T-cell maturation.  

PubMed

Pax1 is a transcriptional regulatory protein expressed during mouse embryogenesis and has been shown to have an important function in vertebral column development. Expression of Pax1 mRNA in the embryonic thymus has been reported previously. Here we show that Pax1 protein expression in thymic epithelial cells can be detected throughout thymic development and in the adult. Expression starts in the early endodermal epithelium lining the foregut region and includes the epithelium of the third pharyngeal pouch, a structure giving rise to part of the thymus epithelium. In early stages of thymus development a large proportion of thymus cells expresses Pax1. With increasing age, the proportion of Pax1-expressing cells is reduced and in the adult mouse only a small fraction of cortical thymic stromal cells retains strong Pax1 expression. Expression of Pax1 in thymus epithelium is necessary for establishing the thymus microenvironment required for normal T cell maturation. Mutations in the Pax-1 gene in undulated mice affect not only the total size of the thymus but also the maturation of thymocytes. The number of thymocytes is reduced about 2- to 5-fold, affecting mainly the CD4+8+ immature and CD4+ mature thymocyte subsets. The expression levels of major thymocyte surface markers remains unchanged with the exception of Thy-1 which was found to be expressed at 3- to 4-fold higher levels. PMID:8565834

Wallin, J; Eibel, H; Neubüser, A; Wilting, J; Koseki, H; Balling, R

1996-01-01

7

Histone deacetylase (HDAC) 1 and 2 are Essential for normal T cell Development and Genomic Stability in Mice  

PubMed Central

Histone deacetylase 1 and 2 (HDAC1/2) regulate chromatin structure as the catalytic core of the Sin3A, NuRD and CoREST co-repressor complexes. To better understand the key pathways regulated by HDAC1/2 in the adaptive immune system and inform their exploitation as drug targets, we have generated mice with a T cell specific deletion. Loss of either HDAC1 or HDAC2 alone has little effect, while dual inactivation results in a 5-fold reduction in thymocyte cellularity, accompanied by developmental arrest at the double-negative to double-positive transition. Transcriptome analysis revealed 892 mis-regulated genes in Hdac1/2 knock-out thymocytes, including down-regulation of LAT, Themis and Itk, key components of the T cell receptor (TCR) signalling pathway. Down-regulation of these genes suggests a model in which HDAC1/2 deficiency results in defective propagation of TCR signalling, thus blocking development. Furthermore, mice with a single Hdac2 allele, develop a lethal pathology by 3-months of age, a result of neoplastic transformation of immature T cells in the thymus. Tumor cells become aneuploid, express increased levels of c-Myc and show elevated levels of the DNA damage marker, ?H2AX. These data demonstrate a crucial role for HDAC1/2 in T cell development and the maintenance of genomic stability.

Dovey, Oliver M.; Foster, Charles T.; Conte, Nathalie; Edwards, Sally A.; Edwards, Jennifer M.; Singh, Rajinder; Vasilliou, George; Bradley, Allan; Cowley, Shaun M.

2013-01-01

8

Histone deacetylase 1 and 2 are essential for normal T-cell development and genomic stability in mice.  

PubMed

Histone deacetylase 1 and 2 (HDAC1/2) regulate chromatin structure as the catalytic core of the Sin3A, NuRD and CoREST co-repressor complexes. To better understand the key pathways regulated by HDAC1/2 in the adaptive immune system and inform their exploitation as drug targets, we have generated mice with a T-cell specific deletion. Loss of either HDAC1 or HDAC2 alone has little effect, while dual inactivation results in a 5-fold reduction in thymocyte cellularity, accompanied by developmental arrest at the double-negative to double-positive transition. Transcriptome analysis revealed 892 misregulated genes in Hdac1/2 knock-out thymocytes, including down-regulation of LAT, Themis and Itk, key components of the T-cell receptor (TCR) signaling pathway. Down-regulation of these genes suggests a model in which HDAC1/2 deficiency results in defective propagation of TCR signaling, thus blocking development. Furthermore, mice with reduced HDAC1/2 activity (Hdac1 deleted and a single Hdac2 allele) develop a lethal pathology by 3-months of age, caused by neoplastic transformation of immature T cells in the thymus. Tumor cells become aneuploid, express increased levels of c-Myc and show elevated levels of the DNA damage marker, ?H2AX. These data demonstrate a crucial role for HDAC1/2 in T-cell development and the maintenance of genomic stability. PMID:23287868

Dovey, Oliver M; Foster, Charles T; Conte, Nathalie; Edwards, Sally A; Edwards, Jennifer M; Singh, Rajinder; Vassiliou, George; Bradley, Allan; Cowley, Shaun M

2013-02-21

9

Normal development and function but impaired memory phenotype of CD8? T cells in transgenic mice expressing HIV-1 Nef in its natural target cells.  

PubMed

We studied the impact of HIV Nef on CD8(+) T cells in a mouse model of AIDS, the CD4C/HIV(Nef) transgenic (Tg) mice. We found that negative and positive thymic selections of CD8(+) T cells proceeded normally in Nef Tg mice bred respectively with HY or OT-1 TCR Tg mice. Tg peripheral CD8(+) T cells showed an activated phenotype and enhanced cell division in vivo and proliferated efficiently when stimulated in vitro with antigenic peptide. When challenged with LCMV(Armstrong), Nef Tg mice developed a strong acute CD8(+) T cell response and cleared the virus as efficiently as wild-type mice. However, maintenance of LCMV-specific CD8(+) memory T cells was impaired in Nef Tg mice, a defect partially rescued by adoptive transfer of non-Tg naïve CD4(+) T cells. Thus, despite severe abnormalities of their precursors, the double-positive CD4(+)CD8(+) thymocytes, Tg CD8(+) T cells have conserved important functions. PMID:23433958

Ahmed Rahim, Mir Munir; Chrobak, Pavel; Priceputu, Elena; Hanna, Zaher; Jolicoeur, Paul

2013-04-10

10

Aire and T cell Development  

PubMed Central

In the thymus, developing T cells that react against self-antigens with high affinity are deleted in the process of negative selection. An essential component of this process is the display of self-antigens, including those whose expression are usually restricted to specific tissues, to developing T cells within the thymus. The Autoimmune Regulator (Aire) gene plays a critical role in the expression of tissue specific self-antigens within the thymus, and disruption of Aire function results in spontaneous autoimmunity in both humans and mice. Recent advances have been made in our understanding of how Aire influences the expression of thousands of tissue-specific antigens in the thymus. Additional roles of Aire, including roles in chemokine and cytokine expression, have also been revealed. Factors important in the differentiation of Aire-expressing medullary thymic epithelial cells have been defined. Finally, the identity of antigen presenting cells in negative selection, including the role of medullary thymic epithelial cells in displaying tissue specific antigens to T cells, has also been clarified.

Anderson, Mark S.; Su, Maureen A.

2011-01-01

11

Activated ?? T Cells Promote the Activation of Uveitogenic T Cells and Exacerbate EAU Development  

PubMed Central

Purpose. To determine how the activation of ?? T cells affects the generation of uveitogenic ?? T cells and the development of experimental autoimmune uveitis (EAU). Methods. ?? T cells were isolated from B6 mice immunized with the uveitogenic peptide IRBP1–20 and ?? T cells from immunized TCR-??/? mice. Resting ?? T cells were prepared by culture of separated ?? T cells in cytokine-free medium for 3 to 5 days, when they showed downregulation of CD69 expression. Activated ?? T cells were prepared by incubating resting ?? T cells with anti-?? TCR (GL3) for 2 days. Responder ?? T cells were cocultured with immunizing antigen and antigen-presenting cells. The numbers of antigen-specific T cells expressing IL-17 or IFN-? were determined by intracellular staining followed by FACS analysis after stimulation, with or without the addition of purified ?? T cells. The cytokines in the culture medium were measured by ELISA. Results. Highly enriched ?? T cells exert widely different effects on autoreactive ?? T cells in EAU, depending on the activation status of the ?? T cells. Whereas nonactivated ?? T cells had little effect on the activation of interphotoreceptor retinoid-binding protein–specific ?? T cells in vitro and in vivo, activated ?? T cells promoted the generation of uveitogenic T cells and exacerbated the development of EAU. Conclusions. The functional ability of ?? T cells is greatly influenced by their activation status. Activated ?? T cells exacerbate EAU through increased activation of uveitogenic T cells.

Nian, Hong; Shao, Hui; O'Brien, Rebecca L.; Born, Willi K.; Kaplan, Henry J.

2011-01-01

12

Extracellular adenosine regulates naive T cell development and peripheral maintenance  

PubMed Central

Adenosine produced as a byproduct of metabolic activity is present in all tissues and produces dose-dependent suppression of TCR signaling. Naive T cell maintenance depends on inhibition of TCR signals by environmental sensors, which are yet to be fully defined. We produced mice with a floxed adenosine A2A receptor (A2AR) gene, Adora2a, and show that either global A2AR deletion or cre-mediated T cell deletion elicits a decline in the number of naive but not memory T cells. A2AR signaling maintains naive T cells in a quiescent state by inhibiting TCR-induced activation of the phosphatidylinositide 3-kinase (PI3K)–AKT pathway, thereby reducing IL-7R? down-regulation and naive T cell apoptosis. Patterns of IL-7R? expression on T cells in chimeric mice reconstituted with Adora2a+/+ and Adora2a?/? bone marrow cells suggest that decreased IL-7R? in naive T cells is a cell-intrinsic consequence of Adora2a deletion. In addition, A2AR expression increases in early thymic T cell development and contributes to progression of double-negative thymic precursors to single-positive thymocytes with increased IL-7R? expression. Therefore, A2AR signaling regulates T cell development and maintenance to sustain normal numbers of naive T cells in the periphery.

Cekic, Caglar; Sag, Duygu; Day, Yuan-Ji

2013-01-01

13

Extrathymic development of murine T cells after bone marrow transplantation  

PubMed Central

Restoring T cell competence is a significant clinical challenge in patients whose thymic function is severely compromised due to age or cytoreductive conditioning. Here, we demonstrate in mice that mesenteric LNs (MLNs) support extrathymic T cell development in euthymic and athymic recipients of bone marrow transplantation (BMT). Furthermore, in aged murine BMT recipients, the contribution of the MLNs to the generation of T cells was maintained, while the contribution of the thymus was significantly impaired. Thymic impairment resulted in a proportional increase in extrathymic-derived T cell progenitors. Extrathymic development in athymic recipients generated conventional naive TCR?? T cells with a broad V? repertoire and intact functional and proliferative potential. Moreover, in the absence of a functional thymus, immunity against known pathogens could be augmented using engineered precursor T cells with viral specificity. These findings demonstrate the potential of extrathymic T cell development for T cell reconstitution in patients with limited thymic function.

Holland, Amanda M.; Zakrzewski, Johannes L.; Tsai, Jennifer J.; Hanash, Alan M.; Dudakov, Jarrod A.; Smith, Odette M.; West, Mallory L.; Singer, Natalie V.; Brill, Jessie; Sun, Joseph C.; van den Brink, Marcel R.M.

2012-01-01

14

T cell immunosurveillance controls B lymphoma development  

PubMed Central

We recently showed a critical role for T cells in the immunosurveillance of nascent B cell lymphomas arising from mutations impacting plasma cell differentiation. Our data suggest that CD8+ T cells continuously eliminate mutated B cells that fail to downregulate their co-stimulatory machinery and the Fas death receptor, thus constraining B lymphoma pathogenesis.

Kallies, Axel

2014-01-01

15

Partial defects of T-cell development associated with poor T-cell function.  

PubMed

For many years, severe combined immune deficiency diseases, which are characterized by virtual lack of circulating T cells and severe predisposition to infections since early in life, have been considered the prototypic forms of genetic defects of T-cell development. More recently, advances in genome sequencing have allowed identification of a growing number of gene defects that cause severe but incomplete defects in T-cell development, function, or both. Along with recurrent and severe infections, especially cutaneous viral infections, the clinical phenotype of these conditions is characterized by prominent immune dysregulation. PMID:23465662

Notarangelo, Luigi D

2013-05-01

16

Partial defects of T cell development associated with poor T cell function  

PubMed Central

For many years, Severe Combined Immune Deficiency (SCID) diseases, characterized by virtual lack of circulating T cells and severe predisposition to infections since early in life, have been considered the prototypic forms of genetic defects of T cell development. More recently, advances in genome sequencing have allowed identification of a growing number of gene defects that cause severe, but incomplete, defects in T cell development and/or function. Along with recurrent and severe infections, and especially cutaneous viral infections, the clinical phenotype of these conditions is characterized by prominent immune dysregulation.

Notarangelo, Luigi D.

2013-01-01

17

MMP19 is essential for T cell development and T cell-mediated cutaneous immune responses.  

PubMed

Matrix metalloproteinase-19 (MMP19) affects cell proliferation, adhesion, and migration in vitro but its physiological role in vivo is poorly understood. To determine the function of MMP19, we generated mice deficient for MMP19 by disrupting the catalytic domain of mmp19 gene. Although MMP19-deficient mice do not show overt developmental and morphological abnormalities they display a distinct physiological phenotype. In a model of contact hypersensitivity (CHS) MMP19-deficient mice showed impaired T cell-mediated immune reaction that was characterized by limited influx of inflammatory cells, low proliferation of keratinocytes, and reduced number of activated CD8(+) T cells in draining lymph nodes. In the inflamed tissue, the low number of CD8(+) T cells in MMP19-deficient mice correlated with low amounts of proinflammatory cytokines, especially lymphotactin and interferon-inducible T cell alpha chemoattractant (I-TAC). Further analyses showed that T cell populations in the blood of immature, unsensitized mice were diminished and that this alteration originated from an altered maturation of thymocytes. In the thymus, thymocytes exhibited low proliferation rates and the number of CD4(+)CD8(+) double-positive cells was remarkably augmented. Based on the phenotype of MMP19-deficient mice we propose that MMP19 is an important factor in cutaneous immune responses and influences the development of T cells. PMID:18523579

Beck, Inken M; Rückert, René; Brandt, Katja; Mueller, Markus S; Sadowski, Thorsten; Brauer, Rena; Schirmacher, Peter; Mentlein, Rolf; Sedlacek, Radislav

2008-01-01

18

MMP19 Is Essential for T Cell Development and T Cell-Mediated Cutaneous Immune Responses  

PubMed Central

Matrix metalloproteinase-19 (MMP19) affects cell proliferation, adhesion, and migration in vitro but its physiological role in vivo is poorly understood. To determine the function of MMP19, we generated mice deficient for MMP19 by disrupting the catalytic domain of mmp19 gene. Although MMP19-deficient mice do not show overt developmental and morphological abnormalities they display a distinct physiological phenotype. In a model of contact hypersensitivity (CHS) MMP19-deficient mice showed impaired T cell-mediated immune reaction that was characterized by limited influx of inflammatory cells, low proliferation of keratinocytes, and reduced number of activated CD8+ T cells in draining lymph nodes. In the inflamed tissue, the low number of CD8+ T cells in MMP19-deficient mice correlated with low amounts of proinflammatory cytokines, especially lymphotactin and interferon-inducible T cell ? chemoattractant (I-TAC). Further analyses showed that T cell populations in the blood of immature, unsensitized mice were diminished and that this alteration originated from an altered maturation of thymocytes. In the thymus, thymocytes exhibited low proliferation rates and the number of CD4+CD8+ double-positive cells was remarkably augmented. Based on the phenotype of MMP19-deficient mice we propose that MMP19 is an important factor in cutaneous immune responses and influences the development of T cells.

Beck, Inken M.; Ruckert, Rene; Brandt, Katja; Mueller, Markus S.; Sadowski, Thorsten; Brauer, Rena; Schirmacher, Peter; Mentlein, Rolf; Sedlacek, Radislav

2008-01-01

19

Relationship between adenosine deaminase activity and cytokine-secreting T cells in normal pregnancy  

Microsoft Academic Search

OBJECTIVE:To evaluate the relationship between plasma adenosine deaminase activity and the proportion of cytokine-secreting T cells as causes of changes in adenosine deaminase activity in normal pregnancy.METHODS:Plasma adenosine deaminase activity and the proportions of cytokine-secreting T cells were measured in the peripheral blood of 26 nonpregnant and normal pregnant women in the third trimester. The proportion of CD4-positive T cells

Yoshio Yoneyama; Rintaro Sawa; Shunji Suzuki; Koichi Yoneyama; Daisuke Doi; Tsutomu Araki

2002-01-01

20

Regulation of Mu Opioid Receptor Expression in Developing T Cells  

PubMed Central

We have previously reported that functionally active ?-opioid receptors (MOR) are constitutively expressed at relatively low levels by developing T cells in the thymus. However, very little is known about the regulation of MOR expression by immature T cells. In this report, we first attempted to determine the effect of T cell receptor-induced T cell activation on the expression of MOR. We activated T cells with either the combination of anti-CD3 and CD28, or with superantigen, and observed a substantial increase in MOR transcript expression. We also chose to examine the effect of cytokine-mediated T cell activation on the expression of this opioid receptor. We selected certain cytokines that play a role in T cell development and are known to be present at functional levels in the thymus gland. Our results show that interferon ? (IFN?), IL-1?, and IL-2, and in particular transforming growth factor-? (TGF?), all induced significant increases in MOR transcript expression. On the other hand, both TNF? and IL-7 exhibited much weaker effects on MOR expression. These results show that MOR expression by developing T cells is strongly regulated by several cytokines involved in T cell development in the thymus gland.

Zhang, Lily; Belkowski, Judith Sliker; Briscoe, Tammi; Rogers, Thomas J.

2012-01-01

21

Role of diacylglycerol kinases in T cell development and function  

PubMed Central

Diacylglycerol (DAG), a second messenger generated by phospholipase C?1 activity upon T cell receptor (TCR) engagement, triggers several signaling cascades that play important roles in T cell development and function. A family of enzymes called diacylglycerol kinases (DGKs) catalyzes the phosphorylation of DAG to phosphatidic acid, acting as a braking mechanism that terminates DAG-mediated signals. Two DGK isoforms, ? and ?, are predominantly expressed in T cells and synergistically regulate the development of both conventional ?? T cells and invariant NKT cells in the thymus. In mature T cells, the activity of these DGK isoforms aids in the maintenance of self-tolerance by preventing T cell hyper-activation upon TCR stimulation and by promoting T cell anergy. In CD8 cells, reduced DGK activity is associated with enhanced primary responses against viruses and tumors. Recent work has also established an important role for DGK activity at the immune synapse and identified partners that modulate DGK function. In addition, emerging evidence points to previously unappreciated roles for DGK function in directional secretion and T cell adhesion. In this review, we discuss the multitude of roles played by DGKs in T cell development and function, while emphasizing recent advances in the field.

Krishna, Sruti

2013-01-01

22

CCR7-mediated migration in the thymus controls ?? T-cell development.  

PubMed

?? T-cell development and selection proceed while thymocytes successively migrate through distinct regions of the thymus. For ?? T cells, the interplay of intrathymic migration and cell differentiation is less well understood. Here, we crossed C-C chemokine receptor (CCR)7-deficient (Ccr7(-/-) ) and CCR9-deficient mice (Ccr9(-/-) ) to mice with a TcrdH2BeGFP reporter background to investigate the impact of thymic localization on ?? T-cell development. ?? T-cell frequencies and numbers were decreased in CCR7-deficient and increased in CCR9-deficient mice. Transfer of CCR7- or CCR9-deficient BM into irradiated C57BL/6 WT recipients reproduced these phenotypes, pointing toward cell-intrinsic migration defects. Monitoring recent thymic emigrants by intrathymic labeling allowed us to identify decreased thymic ?? T-cell output in CCR7-deficient mice. In vitro, CCR7-deficient precursors showed normal ?? T-cell development. Immunohistology revealed that CCR7 and CCR9 expression was important for ?? T-cell localization within thymic medulla or cortex, respectively. However, ?? T-cell motility was unaltered in CCR7- or CCR9-deficient thymi. Together, our results suggest that proper intrathymic localization is important for normal ?? T-cell development. PMID:24500801

Reinhardt, Annika; Ravens, Sarina; Fleige, Henrike; Haas, Jan D; Oberdörfer, Linda; Lyszkiewicz, Marcin; Förster, Reinhold; Prinz, Immo

2014-05-01

23

An overview of the intrathymic intricacies of T cell development.  

PubMed

The generation of a functional and diverse repertoire of T cells occurs in the thymus from precursors arriving from the bone marrow. In this article, we introduce the various stages of mouse thymocyte development and highlight recent work using various in vivo, and, where appropriate, in vitro models of T cell development that led to discoveries in the regulation afforded by transcription factors and receptor-ligand signaling pathways in specifying, maintaining, and promoting the T cell lineage and the production of T cells. This review also discusses the role of the thymic microenvironment in providing a niche for the successful development of T cells. In particular, we focus on advances in Notch signaling and developments in Notch ligand interactions in this process. PMID:24748636

Shah, Divya K; Zúñiga-Pflücker, Juan Carlos

2014-05-01

24

Normal peripheral T-cell function in c-Fos-deficient mice.  

PubMed Central

The ubiquitous transcription factors Fos and Jun are rapidly induced in T cells stimulated through the T-cell antigen receptor and regulate transcription of cytokines, including interleukin 2, in activated T cells. Since positive and negative selection of thymocytes during T-cell development also depends on activation through the T-cell receptor, Fos and Jun may play a role in thymocyte development as well. Fos and Jun act at several regulatory elements in the interleukin 2 promoter, including the AP-1 and NFAT sites. Using antisera specific to individual Fos and Jun family members, we show that c-Fos as well as other Fos family members are present in the inducible AP-1 and NFAT complexes of activated murine T cells. Nevertheless, c-Fos is not absolutely required for the development or function of peripheral T cells, as shown by using mice in which both copies of the c-fos gene were disrupted by targeted mutagenesis. c-Fos-deficient mice were comparable to wild-type mice in their patterns of thymocyte development and in the ability of their peripheral T cells to proliferate and produce several cytokines in response to T-cell receptor stimulation. Our results suggest that other Fos family members may be capable of substituting functionally for c-Fos during T-cell development and cytokine gene transcription in activated T cells. Images

Jain, J; Nalefski, E A; McCaffrey, P G; Johnson, R S; Spiegelman, B M; Papaioannou, V; Rao, A

1994-01-01

25

Egr3 Induces a Th17 Response by Promoting the Development of ?? T Cells  

PubMed Central

The transcription factor Early Growth Response 3 (Egr3) has been shown to play an important role in negatively regulating T cell activation and promoting T cell anergy in Th1 cells. However, its role in regulating other T helper subsets has yet to be described. We sought to determine the role of Egr3 in a Th17 response using transgenic mice that overexpress Egr3 in T cells (Egr3 TG). Splenocytes from Egr3 TG mice demonstrated more robust generation of Th17 cells even under non-Th17 skewing conditions. We found that while Egr3 TG T cells were not intrinsically more likely to become Th17 cells, the environment encountered by these cells was more conducive to Th17 development. Further analysis revealed a considerable increase in the number of ?? T cells in both the peripheral lymphoid organs and mucosal tissues of Egr3 TG mice, a cell type which normally accounts for only a small fraction of peripheral lymphocytes. Consistent with this marked increase in peripheral ?? T cells, thymocytes from Egr3 TG mice also appear biased toward ?? T cell development. Coculture of these Egr3-induced ?? T cells with wildtype CD4+ T cells increases Th17 differentiation, and Egr3 TG mice are more susceptible to bleomycin-induced lung inflammation. Overall our findings strengthen the role for Egr3 in promoting ?? T cell development and show that Egr3-induced ?? T cells are both functional and capable of altering the adaptive immune response in a Th17-biased manner. Our data also demonstrates that the role played by Egr3 in T cell activation and differentiation is more complex than previously thought.

Parkinson, Rose M.; Collins, Samuel L.; Horton, Maureen R.; Powell, Jonathan D.

2014-01-01

26

Differential requirement for CARMA1 in agonist-selected T-cell development.  

PubMed

Caspase recruitment domain-containing membrane-associated guanylate kinase protein-1 (CARMA1) is a critical component of the NF-kappaB signaling cascade mediated by TCR engagement. In addition to activation of naïve T cells, TCR signaling is important for the development of agonist-selected T-cell subsets such as Treg, NKT cells, and CD8-alpha alpha T cells. However, little is known about the role of CARMA1 in the development of these lineages. Here we show that CARMA1-deficient mice (CARMA1(-/-)) have altered populations of specific subsets of agonist-selected T cells. Specifically, CARMA1(-/-) mice have impaired natural and adaptive Treg development, whereas NKT cell numbers are normal compared with wild-type mice. Interestingly, CD8-alpha alpha T cells, which may also be able to develop through an extrathymic selection pathway, are enriched in the gut of CARMA1(-/-) mice, whereas memory-phenotype CD4(+) T cells (CD62L(low)/CD44(high)) are present at reduced numbers in the periphery. These results indicate that CARMA1 is essential for Treg development, but is not necessary for the development of other agonist-selected T-cell subsets. Overall, these data reveal an important but differential role for CARMA1-mediated TCR signaling in T-cell development. PMID:19130560

Medoff, Benjamin D; Sandall, Barry P; Landry, Aimee; Nagahama, Kiyotaka; Mizoguchi, Atsushi; Luster, Andrew D; Xavier, Ramnik J

2009-01-01

27

Activated Akt promotes increased resting T cell size, CD28-independent T cell growth, and development of autoimmunity and lymphoma.  

PubMed

The mechanisms that regulate basal T cell size and metabolic activity are uncertain. Since the phosphatidylinositol-3 phosphate kinase (PI3 K) and Akt (PKB) pathway has been shown in model organisms to regulate both cell size and metabolism, we generated transgenic mice expressing a constitutively active form of Akt (myristoylated Akt, mAkt) in T cells. Naive transgenic T cells were enlarged and had increased rates of glycolysis compared to control T cells. In addition, mAkt transgenic T cells resisted death-by-neglect upon in vitro culture. Upon activation, mAkt-transgenic T cells were less dependent than control cells on costimulation through CD28 and could both grow rapidly and secrete cytokines in the absence of CD28 ligation. In addition, transgenic expression of mAkt led to the accumulation of CD4 T cells and B cells with age. Many aged mAkt-transgenic mice also developed autoimmunity with immunoglobulin deposits on kidney glomeruli and displayed increased incidence of lymphoma. Together, these data show that Akt activation is sufficient to increase basal T cell size and metabolism. Enhancement of T cell metabolism by Akt and more rapid CD28-independent T cell growth may contribute to the accumulation of excess immune cells and the development of lymphoma and autoimmunity. PMID:12884297

Rathmell, Jeffrey C; Elstrom, Rebecca L; Cinalli, Ryan M; Thompson, Craig B

2003-08-01

28

Sin1 regulates Treg development but is not required for T cell growth and proliferation  

PubMed Central

Summary Mammalian Sin1 plays key roles in the regulation of mitogen activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling. Sin1 is an essential component of mTOR complex (mTORC) 2. The function of Sin1 and mTORC2 remains largely unknown in T cells. Here we investigate Sin1 function in T cells using mice which lack Sin1 in the hematopoietic system. Sin1 deficiency blocks the mTORC2 dependent Akt phosphorylation in T cells during development and activation. Sin1 deficient T cells exhibit normal thymic cellularity and percentages of double negative, double positive and single positive CD4 and CD8 thymocytes. Sin1 deficiency does not impair T cell receptor (TCR) induced growth and proliferation, and normal CD4+ helper cell differentiation. However Sin1 deficiency results in an increased proportion of Foxp3+ natural T regulatory (nTreg) cells in the thymus. We show that the TGF-? dependent differentiation of CD4+ T cells in vitro is enhanced by the inhibition of mTOR but not loss of Sin1 function. Our results reveal that Sin1 and mTORC2 are dispensable for the development and activation of T cells but play a role in natural Treg cell differentiation.

Chang, Xing; Lazorchak, Adam S.; Liu, Dou; Su, Bing

2013-01-01

29

Donor T-cell alloreactivity against host thymic epithelium limits T-cell development after bone marrow transplantation.  

PubMed

Acute graft-versus-host disease (aGVHD) impairs thymus-dependent T-cell regeneration in recipients of allogeneic bone marrow transplants through yet to be defined mechanisms. Here, we demonstrate in mice that MHC-mismatched donor T cells home into the thymus of unconditioned recipients. There, activated donor T cells secrete IFN-gamma, which in turn stimulates the programmed cell death of thymic epithelial cells (TECs). Because TECs themselves are competent and sufficient to prime naive allospecific T cells and to elicit their effector function, the elimination of host-type professional antigen-presenting cells (APCs) does not prevent donor T-cell activation and TEC apoptosis, thus precluding normal thymopoiesis in transplant recipients. Hence, strategies that protect TECs may be necessary to improve immune reconstitution following allogeneic bone marrow transplantation. PMID:17213290

Hauri-Hohl, Mathias M; Keller, Marcel P; Gill, Jason; Hafen, Katrin; Pachlatko, Esther; Boulay, Thomas; Peter, Annick; Holländer, Georg A; Krenger, Werner

2007-05-01

30

Donor T-cell alloreactivity against host thymic epithelium limits T-cell development after bone marrow transplantation  

PubMed Central

Acute graft-versus-host disease (aGVHD) impairs thymus-dependent T-cell regeneration in recipients of allogeneic bone marrow transplants through yet to be defined mechanisms. Here, we demonstrate in mice that MHC-mismatched donor T cells home into the thymus of unconditioned recipients. There, activated donor T cells secrete IFN-?, which in turn stimulates the programmed cell death of thymic epithelial cells (TECs). Because TECs themselves are competent and sufficient to prime naive allospecific T cells and to elicit their effector function, the elimination of host-type professional antigen-presenting cells (APCs) does not prevent donor T-cell activation and TEC apoptosis, thus precluding normal thymopoiesis in transplant recipients. Hence, strategies that protect TECs may be necessary to improve immune reconstitution following allogeneic bone marrow transplantation.

Hauri-Hohl, Mathias M.; Keller, Marcel P.; Gill, Jason; Hafen, Katrin; Pachlatko, Esther; Boulay, Thomas; Peter, Annick; Hollander, Georg A.

2007-01-01

31

Jurkat T cells and development of the T-cell receptor signalling paradigm  

Microsoft Academic Search

Twenty years of investigation have yielded a detailed view of the signalling machinery engaged by T-cell receptors (TCRs). Many of the fundamental insights into TCR signalling came from studies carried out with transformed T-cell lines. Perhaps the best known of these model systems is the Jurkat leukaemic T-cell line, and here we review some of the key advances in the

Arthur Weiss; Robert T. Abraham

2004-01-01

32

Extrathymic development of V alpha 14-positive T cells  

PubMed Central

It is known that rearrangement of the T cell antigen receptor (TCR) gene occurs in the thymus during T cell development and consequently results both in the deletion of DNA between the variable (V) and diversity/joining segments and in the formation of a circular DNA with recombination signal sequences. Here, we provide evidence that V alpha 14+ TCR gene rearrangements take place in extrathymic sites, such as bone marrow, liver, and intestine, but not in spleen, because we were able to detect frequent productive and nonproductive V alpha 14+ coding and signal sequences as a result of TCR rearrangements in extrathymic sites. Similar findings were also detected in athymic mice. Quantitative analysis shows that the relative amounts of V alpha 14 gene-mediated signal sequences in extrathymic tissues are higher than those in thymus. On the contrary, TCR rearrangements of V alpha 1.1 T cells, which are known to develop in the thymus, were mainly detected in the thymus, Peyer's patch, and spleen, but not in other extrathymic tissues, showing patterns distinct from V alpha 14 TCR rearrangements. These findings are evidence of extrathymic development of V alpha 14+ T cells. Differential characteristic TCR rearrangement patterns also indicate that distinct TCR repertoires are generated in different lymphoid tissues.

1993-01-01

33

Normal T-Cell Turnover in Sooty Mangabeys Harboring Active Simian Immunodeficiency Virus Infection  

PubMed Central

Sooty mangabeys naturally infected with simian immunodeficiency virus (SIV) remain healthy though they harbor viral loads comparable to those in rhesus macaques that progress to AIDS. To assess the immunologic basis of disease resistance in mangabeys, we compared the effect of SIV infection on T-cell regeneration in both monkey species. Measurement of the proliferation marker Ki-67 by flow cytometry showed that mangabeys harbored proliferating T cells at a level of 3 to 4% in peripheral blood irrespective of their infection status. In contrast, rhesus macaques demonstrated a naturally high fraction of proliferating T cells (7%) that increased two- to threefold following SIV infection. Ki-67+ T cells were predominantly CD45RA?, indicating increased proliferation of memory cells in macaques. Quantitation of an episomal DNA product of T-cell receptor ? rearrangement (termed ?1 circle) showed that the concentration of recent thymic emigrants in blood decreased with age over a 2-log unit range in both monkey species, consistent with age-related thymic involution. SIV infection caused a limited decrease of ?1 circle numbers in mangabeys as well as in macaques. Dilution of ?1 circles by T-cell proliferation likely contributed to this decrease, since ?1 circle numbers and Ki-67+ fractions correlated negatively. These findings are compatible with immune exhaustion mediated by abnormal T-cell proliferation, rather than with early thymic failure, in SIV-infected macaques. Normal T-cell turnover in SIV-infected mangabeys provides an explanation for the long-term maintenance of a functional immune system in these hosts.

Chakrabarti, Lisa A.; Lewin, Sharon R.; Zhang, Linqi; Gettie, Agegnehu; Luckay, Amara; Martin, Louis N.; Skulsky, Eva; Ho, David D.; Cheng-Mayer, Cecilia; Marx, Preston A.

2000-01-01

34

The Liver Kinase B1 (LKB1) is a central regulator of T cell development, activation, and metabolism  

PubMed Central

T cell activation leads to engagement of cellular metabolic pathways necessary to support cell proliferation and function. However, our understanding of the signal transduction pathways that regulate metabolism and their impact on T cell function remains limited. The Liver Kinase B1 (LKB1) is a serine/threonine kinase that links cellular metabolism with cell growth and proliferation. Here we demonstrate that LKB1 is a critical regulator of T cell development, viability, activation, and metabolism. T cell-specific ablation of the gene that encodes LKB1 resulted in blocked thymocyte development and a reduction in peripheral T cells. LKB1-deficient T cells exhibited defects in cell proliferation and viability, and altered glycolytic and lipid metabolism. Interestingly, loss of LKB1 promoted increased T cell activation and inflammatory cytokine production by both CD4+ and CD8+ T cells. Activation of the AMP-activated protein kinase (AMPK) was decreased in LKB1-deficient T cells. AMPK was found to mediate a subset of LKB1 functions in T lymphocytes, as mice lacking the ?1 subunit of AMPK displayed similar defects in T cell activation, metabolism, and inflammatory cytokine production, but normal T cell development and peripheral T cell homeostasis. LKB1- and AMPK?1-deficient T cells each displayed elevated mTORC1 signaling and IFN-? production that could be reversed by rapamycin treatment. Our data highlight a central role for LKB1 in T cell activation, viability, and metabolism, and suggest that LKB1-AMPK signaling negatively regulates T cell effector function through regulation of mTOR activity.

MacIver, Nancie J.; Blagih, Julianna; Saucillo, Donte C.; Tonelli, Luciana; Griss, Takla; Rathmell, Jeffrey C.; Jones, Russell G.

2011-01-01

35

Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients  

PubMed Central

Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE) have multiple defects in lymphocyte signaling and function that contribute to disease pathogenesis. Such defects could be attributed to alterations in metabolic processes, including abnormal control of lipid biosynthesis pathways. Here, we reveal that CD4+ T cells from SLE patients displayed an altered profile of lipid raft–associated glycosphingolipids (GSLs) compared with that of healthy controls. In particular, lactosylceramide, globotriaosylceramide (Gb3), and monosialotetrahexosylganglioside (GM1) levels were markedly increased. Elevated GSLs in SLE patients were associated with increased expression of liver X receptor ? (LXR?), a nuclear receptor that controls cellular lipid metabolism and trafficking and influences acquired immune responses. Stimulation of CD4+ T cells isolated from healthy donors with synthetic and endogenous LXR agonists promoted GSL expression, which was blocked by an LXR antagonist. Increased GSL expression in CD4+ T cells was associated with intracellular accumulation and accelerated trafficking of GSL, reminiscent of cells from patients with glycolipid storage diseases. Inhibition of GSL biosynthesis in vitro with a clinically approved inhibitor (N-butyldeoxynojirimycin) normalized GSL metabolism, corrected CD4+ T cell signaling and functional defects, and decreased anti-dsDNA antibody production by autologous B cells in SLE patients. Our data demonstrate that lipid metabolism defects contribute to SLE pathogenesis and suggest that targeting GSL biosynthesis restores T cell function in SLE.

McDonald, Georgia; Deepak, Shantal; Miguel, Laura; Hall, Cleo J.; Isenberg, David A.; Magee, Anthony I.; Butters, Terry; Jury, Elizabeth C.

2014-01-01

36

Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients.  

PubMed

Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE) have multiple defects in lymphocyte signaling and function that contribute to disease pathogenesis. Such defects could be attributed to alterations in metabolic processes, including abnormal control of lipid biosynthesis pathways. Here, we reveal that CD4+ T cells from SLE patients displayed an altered profile of lipid raft-associated glycosphingolipids (GSLs) compared with that of healthy controls. In particular, lactosylceramide, globotriaosylceramide (Gb3), and monosialotetrahexosylganglioside (GM1) levels were markedly increased. Elevated GSLs in SLE patients were associated with increased expression of liver X receptor ? (LXR?), a nuclear receptor that controls cellular lipid metabolism and trafficking and influences acquired immune responses. Stimulation of CD4+ T cells isolated from healthy donors with synthetic and endogenous LXR agonists promoted GSL expression, which was blocked by an LXR antagonist. Increased GSL expression in CD4+ T cells was associated with intracellular accumulation and accelerated trafficking of GSL, reminiscent of cells from patients with glycolipid storage diseases. Inhibition of GSL biosynthesis in vitro with a clinically approved inhibitor (N-butyldeoxynojirimycin) normalized GSL metabolism, corrected CD4+ T cell signaling and functional defects, and decreased anti-dsDNA antibody production by autologous B cells in SLE patients. Our data demonstrate that lipid metabolism defects contribute to SLE pathogenesis and suggest that targeting GSL biosynthesis restores T cell function in SLE. PMID:24463447

McDonald, Georgia; Deepak, Shantal; Miguel, Laura; Hall, Cleo J; Isenberg, David A; Magee, Anthony I; Butters, Terry; Jury, Elizabeth C

2014-02-01

37

Essential Role of LAT in T Cell Development  

Microsoft Academic Search

The linker molecule LAT is a substrate of the tyrosine kinases activated following TCR engagement. Phosphorylated LAT binds many critical signaling molecules. The central role of this molecule in TCR-mediated signaling has been demonstrated by experiments in a LAT-deficient cell line. To probe the role of LAT in T cell development, the LAT gene was disrupted by targeting. LAT-deficient mice

Weiguo Zhang; Connie L Sommers; Deborah N Burshtyn; Christopher C Stebbins; Jan B DeJarnette; Ronald P Trible; Alexander Grinberg; Henry C Tsay; Helena M Jacobs; Craig M Kessler; Eric O Long; Paul E Love; Lawrence E Samelson

1999-01-01

38

Lymphoid Development in Mice Congenitally Lacking T Cell Receptor alphabeta-Expressing Cells  

Microsoft Academic Search

Vertebrate T cells express either an alphabeta or gammadelta T cell receptor (TCR). The developmental relatedness of the two cell types is unresolved. alphabeta^+ T cells respond to specific pathogens by collaborating with immunoglobulin-producing B cells in distinct lymphoid organs such as the spleen and Peyer's patches. The precise influence of alphabeta^+ T cells on B cell development is poorly

Karen L. Philpott; Joanne L. Viney; Graham Kay; Sohaila Rastan; Edith M. Gardiner; Sarah Chae; Adrian C. Hayday; Michael J. Owen

1992-01-01

39

The Effects of TLR Activation on T-Cell Development and Differentiation  

PubMed Central

Invading pathogens have unique molecular signatures that are recognized by Toll-like receptors (TLRs) resulting in either activation of antigen-presenting cells (APCs) and/or costimulation of T cells inducing both innate and adaptive immunity. TLRs are also involved in T-cell development and can reprogram Treg cells to become helper cells. T cells consist of various subsets, that is, Th1, Th2, Th17, T follicular helper (Tfh), cytotoxic T lymphocytes (CTLs), regulatory T cells (Treg) and these originate from thymic progenitor thymocytes. T-cell receptor (TCR) activation in distinct T-cell subsets with different TLRs results in differing outcomes, for example, activation of TLR4 expressed in T cells promotes suppressive function of regulatory T cells (Treg), while activation of TLR6 expressed in T cells abrogates Treg function. The current state of knowledge of regarding TLR-mediated T-cell development and differentiation is reviewed.

Jin, Bo; Sun, Tao; Yu, Xiao-Hong; Yang, Ying-Xiang; Yeo, Anthony E. T.

2012-01-01

40

Undermethylation of interferon-gamma gene in human T cell lines and normal T lymphocytes.  

PubMed

The relative levels of DNA methylation at CCGG sequences within and around the interferon-gamma (IFN-gamma) gene in normal human tissues and cell lines were examined by Southern blot analysis using isoschizomeric restriction enzymes, HpaII and MspI. On the test of normal tissues, the IFN-gamma gene was undermethylated only in a small population of T lymphocyte, whereas the gene was fully methylated in T cell-depleted lymphocytes and uterus cells. In TCL-Fuj cell line which is a T cell line producing a high level of IFN-gamma spontaneously, the IFN-gamma gene was undermethylated. Moreover, the extent of DNA methylation was inversely correlated to the level of expression of the IFN-gamma gene in several T cell lines including sublines derived from TCL-Fuj cells. However, partial or complete unmethylation at the CCGG sites of IFN-gamma gene was observed in a promyelocytic leukemia cell line and two epithelial cell lines that fail to produce IFN-gamma irrespective of induction. These results suggest that undermethylation of IFN-gamma gene is necessary but not sufficient for its efficient expression. PMID:3086842

Fukunaga, R; Matsuyama, M; Okamura, H; Nagata, K; Nagata, S; Sokawa, Y

1986-06-11

41

Enhancement of growth of a radiation-induced lymphoma by T cells from normal mice.  

PubMed Central

The effect of lymphocytes from normal mice on the growth of a syngeneic, radiation-induced, T-cell-derived lymphoma was investigated. Thymus and spleen cells enhanced the growth of admixed lymphoma cells in a reproducible manner. Growth enhancement was manifested by the earlier appearance and higher final incidence of tumours. Lymphocytes also enhanced the growth of radiation-damaged lymphoma cells. The enhancing activity of spleen cells was predominantly a property of T cells, since it was abolished by treatment with anti-theta serum plus complement and significantly less in spleen cells of nude mice. Tumour-enhancing thymocytes seem to belong to the immature thymic subpopulation, as indicated by their binding to peanut agglutinin.

Gabizon, A.; Trainin, N.

1980-01-01

42

Oligoclonal expression of T-cell receptor Beta variable genes in normal human endometrium.  

PubMed

In spite of their key role in various immunological processes occurring in the endometrium, T cells- especially ab+ subtype- residing in this mucosal tissue, have not been extensively explored. We present here the profile of expressed genes for variable region of b chain of T cell receptor (TCR) in normal endometrium as compared to peripheral blood. Samples from endometrium were taken from normal fertile women during routine check-up by Pipelle pipette or after hysterectomy operation. Total RNA from both blood and endometrial samples was extracted and RT-PCR using BV gene specific primers was performed. After southern blotting, hybridization with radiolabelled specific probe and autoradiography, relative expression of each BV family was determined. Clonal expansions of the over-expressed genes were studied by determining their CDR3 length polymorphism. A total of 12 blood and 14 endometrial samples were collected. Only one TCRBV gene (TCRBV7) was expressed significantly more and 3 genes less frequently in the endometrium compared to blood. Also, two other genes (TCRBV10 and 12) were found marginally more frequent in the endometrium. As for their clonality, all 3 TCRBV genes examined here showed a rather restricted (oligoclonal) and in some cases, very restricted (probably monoclonal) pattern in the endometrium in contrast to polyclonal patterns in the blood. Our results indicate the similarities between T cells residing in different mucosal tissues and support their common recruitment and functional potentials. Moreover, our findings provide a basis for future investigations about endometrial T cell involvement and their antigen specificities in different gynecological problems. PMID:17301425

Dokouhaki, Pouneh; Razavi, Alireza; Moghaddam, Rosa; Akbariasbagh, Firoozeh; Ghaffari Novin, Marefat; Zarnani, Amirhassan; Jeddi Tehrani, Mahmood

2005-06-01

43

Tec family kinases: Itk signaling and the development of NKT ?? and ?? T cells.  

PubMed

The Tec family tyrosine kinase interleukin-2 inducible T-cell kinase (Itk) is predominantly expressed in T cells and has been shown to be critical for the development, function and differentiation of conventional ?? T cells. However, less is known about its role in nonconventional T cells such as NKT and ?? T cells. In this minireview, we discuss evidence for a role for Itk in the development of invariant NKT ?? cells, as well as a smaller population NKT-like ?? T cells. We discuss how these cells take what could be the same signaling pathway regulated by Itk, and interpret it to give different outcomes with regards to development and function. PMID:21362141

Qi, Qian; Kannan, Arun Kumar; August, Avery

2011-06-01

44

Statistical Physics of T-Cell Development and Pathogen Specificity  

NASA Astrophysics Data System (ADS)

In addition to an innate immune system that battles pathogens in a nonspecific fashion, higher organisms, such as humans, possess an adaptive immune system to combat diverse (and evolving) microbial pathogens. Remarkably, the adaptive immune system mounts pathogen-specific responses, which can be recalled upon reinfection with the same pathogen. It is difficult to see how the adaptive immune system can be preprogrammed to respond specifically to a vast and unknown set of pathogens. Although major advances have been made in understanding pertinent molecular and cellular phenomena, the precise principles that govern many aspects of an immune response are largely unknown. We discuss complementary approaches from statistical mechanics and cell biology that can shed light on how key components of the adaptive immune system, T cells, develop to enable pathogen-specific responses against many diverse pathogens. The mechanistic understanding that emerges has implications for how host genetics may influence the development of T cells with differing responses to the human immunodeficiency virus (HIV) infection.

Košmrlj, Andrej; Kardar, Mehran; Chakraborty, Arup K.

2013-04-01

45

Foxo transcription factors control regulatory T cell development and function  

PubMed Central

SUMMARY Foxo transcription factors integrate extrinsic signals to regulate cell division, differentiation and survival, and specific functions of lymphoid and myeloid cells. Here we showed the absence of Foxo1 severely curtailed the development of Foxp3+ regulatory T (Treg) cells, and those that developed were nonfunctional in vivo. The loss of function included diminished CTLA-4 receptor expression as the Ctla4 gene was a direct target of Foxo1. T cell specific loss of Foxo1 resulted in exocrine pancreatitis, hind limb paralysis, multi-organ lymphocyte infiltration, anti-nuclear antibodies and expanded germinal centers. Foxo-mediated control over Treg cell specification was further revealed by the inability of TGF-? cytokine to suppress T-bet transcription factor in the absence of Foxo1, resulting in IFN-?-secretion. In addition the absence of Foxo3 exacerbated the effects of the loss of Foxo1. Thus, Foxo transcription factors guide the contingencies of T cell differentiation and specific functions of effector cell populations.

Kerdiles, Yann M.; Stone, Erica L.; Beisner, Daniel L.; McGargill, Maureen A.; Ch'en, Irene L.; Stockmann, Christian; Katayama, Carol D.; Hedrick, Stephen M.

2010-01-01

46

IL5Deficient Mice Have a Developmental Defect in CD5 + B1 Cells and Lack Eosinophilia but Have Normal Antibody and Cytotoxic T Cell Responses  

Microsoft Academic Search

Mice deficient in interleukin-5 (IL-5?\\/? mice) were generated by gene targeting in embryonal stem cells. Contrary to previous studies, no obligatory role for IL-5 was demonstrated in the regulation of conventional B (B-2) cells, in normal T cell–dependent antibody responses or in cytotoxic T cell development. However, CD5+ B cells (B-1 cells) in the peritoneal cavity were reduced by 50%–80%

Manfred Kopf; Frank Brombacher; Philip D Hodgkin; Alistair J Ramsay; Elizabeth A Milbourne; Wen J Dai; Karen S Ovington; Carolyn A Behm; Georges Köhler; Ian G Young; Klaus I Matthaei

1996-01-01

47

T cell ageing: effects of age on development, survival & function.  

PubMed

Age associated decline of the immune system continues to be a major health concern. All components of innate and adaptive immunity are adversely affected to lesser or greater extent by ageing resulting in an overall decline of immunocompetence. As a result in the aged population, there is increased susceptibility to infection, poor responses to vaccination, and increased incidence of autoreactivity. There is an increasing focus on the role of T cells during ageing because of their impact on the overall immune responses. A steady decline in the production of fresh naïve T cells, more restricted T cell receptor (TCR) repertoire and weak activation of T cells are some of the effects of ageing. In this review we summarize our present understanding of the effects of ageing on naïve CD4 T cells and potential approaches for therapeutic interventions to restore protective immunity in the aged population. PMID:24434315

Salam, Nasir; Rane, Sanket; Das, Rituparna; Faulkner, Matthew; Gund, Rupali; Kandpal, Usha; Lewis, Virginia; Mattoo, Hamid; Prabhu, Savit; Ranganathan, Vidya; Durdik, Jeannine; George, Anna; Rath, Satyajit; Bal, Vineeta

2013-11-01

48

PD-1 regulates T cell proliferation in a tissue and subset specific manner during normal mouse pregnancy  

PubMed Central

The regulation of T cell homeostasis during pregnancy has important implications for maternal tolerance and immunity. Evidence suggests that Programmed Death-1 (PD-1) participates in regulation of T cell homeostasis and peripheral tolerance. To examine the contribution of PD-1 signaling on T cell homeostasis during normal mouse pregnancy, we examined T cell number or proportion, PD-1 expression, proliferation, and apoptosis by flow cytometry, BrdU incorporation, and TUNEL assay in pregnant mice given anti-PD-1 blocking antibody or control on days 10, 12, and 14 of gestation. We observed tissue, treatment, and T cell-specific differences in PD-1 expression. Both pregnancy and PD-1 blockade increased T cell proliferation in the spleen while this effect was limited to CD4 T cells in the uterine- draining nodes. In the uterus, PD-1 blockade markedly altered the composition of the T cell pool. These studies support the idea that pregnancy is a state of dynamic T cell homeostasis and suggest that this state is partially supported by PD-1 signaling.

Shepard, Michelle T.; Bonney, Elizabeth A.

2014-01-01

49

Reduced thymic maturation but normal effector function of CD8+ T cells in CD8 beta gene-targeted mice  

PubMed Central

CD8 is a cell surface glycoprotein on major histocompatibility complex class I-restricted T cells. Thymocytes and most peripheral T cells express CD8 as heterodimers of CD8 alpha and CD8 beta. The intestinal intraepithelial lymphocytes (IEL), which have been suggested to be generated extrathymically, express CD8 predominantly as homodimers of CD8 alpha. We have generated CD8 beta gene-targeted mice. CD8 alpha+ T cell population in the thymus and in most peripheral lymphoid organs was reduced to 20-30% of that in wild-type littermates. CD8 alpha expression on thymocytes and peripheral T cells also decreased to 44 and 53% of the normal levels, respectively. In contrast, neither the population size nor the CD8 alpha expression level of CD8 alpha+ IEL was reduced. This finding indicates that CD8 beta is important only for thymic-derived CD8+ T cells. The lack of CD8 beta reduces but does not completely abolish thymic maturation of CD8+ T cells. Our result also reveals the role of CD8 beta in regulating CD8 alpha expression on thymic derived T cells. Peripheral T cells in these mice were efficient in cytotoxic activity against lymphocytic choriomeningitis virus and vesicular stomatitis virus, suggesting that CD8 beta is not essential for the effector function of CD8+ T cells.

1994-01-01

50

T-cell receptor-gamma/delta bearing lymphocytes in normal and inflammatory human skin.  

PubMed

Murine dendritic epidermal T cells (DETC) were recently reported to express T-cell receptor (TCR)-gamma/delta chains. In a search for the human equivalent of these cells, we tested normal and lesional skin with MoAb which react with the TCR-gamma/delta heterodimer. We performed indirect immunofluorescence (IF) on epidermal sheets, and alkaline-phosphatase-anti-alkaline-phosphatase complex (APAAP) on epidermal cell smears. Frozen skin sections from normal skin and various cutaneous lymphocyte infiltrates were also studied. A few CD3+ T lymphocytes were consistently found in normal epidermis. Most of these cells appeared to be TCR-alpha/beta +, and some CD4+ or CD8+. On epidermal sheets and cell smears, only a very small TCR-gamma/delta + cell population was visualized (less than 0.1% of the total). On normal skin sections, we observed 0 to 3 gamma/delta + cells per section. When present, they were often located in the epidermal basal layer, and were round or dendritic. Double immunolabeling revealed that gamma/delta + cells differed from CD1+ Langerhans cells, and that they had a similar phenotypic pattern as gamma/delta + peripheral lymphocytes (PBL): CD2+, CD3+, CD4-, and CD8-. Immunostaining from various inflammatory skin lesions showed that the dermal infiltrates included CD3+ T lymphocytes but virtually no gamma/delta + cells. Only a few gamma/delta + cells were found in some end-evolutive infiltrates. Taken together, these results strongly suggest that normal human epidermis occasionally harbors TCR-gamma/delta complex bearing lymphocytes, which constitute a small fraction of the CD3+ cutaneous T lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2141342

Dupuy, P; Heslan, M; Fraitag, S; Hercend, T; Dubertret, L; Bagot, M

1990-06-01

51

Expression of NFAT-family proteins in normal human T cells.  

PubMed Central

NFAT proteins constitute a family of transcription factors involved in mediating signal transduction. Using a panel of specific antisera in immunoprecipitation assays, we found that NFATp (135 kDa) is constitutively expressed in normal human T cells, while synthesis of NFATc (predominant form of 86 kDa) is induced by ionomycin treatment. NFAT4/x was very weakly expressed in unstimulated cells, and its level did not increase upon treatment with activating agents. NFAT3 protein was not observed under any conditions. Higher-molecular-weight species of NFATc (of 110 and 140 kDa) were also detected. In addition, translation of NFATc mRNA apparently initiates at two different AUG codons, giving rise to proteins that differ in size by 36 amino acids. Additional size heterogeneity of both NFATc and NFATp results from phosphorylation. In contrast to ionomycin treatment, exposure of cells to phorbol myristate acetate (PMA) plus anti-CD28 did not induce NFATc, indicating that under these conditions, interleukin-2 synthesis by these cells is apparently independent of NFATc. In DNA binding assays, both PMA plus anti-CD28 and PMA plus ionomycin resulted in nuclear NFAT. Surprisingly, the PMA-ionomycin-induced synthesis of NFATc that was detected by immunoprecipitation was not mirrored in the DNA binding assays: nearly all of the activity was due to NFATp. This is the first study of expression of all family members at the protein level in normal human T cells.

Lyakh, L; Ghosh, P; Rice, N R

1997-01-01

52

Regulatory T cells and their role in rheumatic diseases: a potential target for novel therapeutic development  

PubMed Central

Regulatory T cells have an important role in limiting immune reactions and are essential regulators of self-tolerance. Among them, CD4+CD25high regulatory T cells are the best-described subset. In this article, we summarize current knowledge on the phenotype, function, and development of CD4+CD25high regulatory T cells. We also review the literature on the role of these T cells in rheumatic diseases and discuss the potential for their use in immunotherapy.

Milojevic, Diana; Nguyen, Khoa D; Wara, Diane; Mellins, Elizabeth D

2008-01-01

53

Critical roles of lysosomal acid lipase in T cell development and function.  

PubMed

Lysosomal acid lipase (LAL) cleaves cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in lysosomes. In LAL gene-knockout (lal(-/-)) mice, blockage of cholesteryl ester and triglyceride metabolism led to abnormal organization of the thymus and spleen, as well as neutral lipid accumulation in these organs. LAL deficiency impaired T cell development in the thymus. Peripheral T cells were reduced dramatically in lal(-/-) mice, due largely to increased apoptosis and decreased proliferation of lal(-/-) T cells in the thymus and peripheral compartments. These lal(-/-) T cells lost the ability to respond to T cell receptor stimulation, including reduced expression of cell surface receptor CD69, abolishment of T cell proliferation, and decreased expression of T lymphokines after stimulation by either anti-CD3 plus anti-CD28 or phorbol-12-myristate-13-acetate and ionomycin. Differentiation of Th1 and Th2 CD4(+) effector lymphocytes by T cell receptor stimulation was blocked in lal(-/-) mice. The ratio of CD4(+)CD25(+)FoxP3(+) Tregs to CD4(+) T cells was increased in lal(-/-) spleens. Bone marrow chimeras demonstrated retardation of T cell development and maturation in lal(-/-) mice due to defects in T cell precursors. Therefore, LAL, its downstream genes, and lipid mediators all play essential roles in development, homeostasis, and function of T cells. The altered development and function of lal(-/-) T cells contributes to disease formation in various organs during LAL deficiency. PMID:19179613

Qu, Peng; Du, Hong; Wilkes, David S; Yan, Cong

2009-03-01

54

Critical Roles of Lysosomal Acid Lipase in T Cell Development and Function  

PubMed Central

Lysosomal acid lipase (LAL) cleaves cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in lysosomes. In LAL gene-knockout (lal?/?) mice, blockage of cholesteryl ester and triglyceride metabolism led to abnormal organization of the thymus and spleen, as well as neutral lipid accumulation in these organs. LAL deficiency impaired T cell development in the thymus. Peripheral T cells were reduced dramatically in lal?/? mice, due largely to increased apoptosis and decreased proliferation of lal?/? T cells in the thymus and peripheral compartments. These lal?/? T cells lost the ability to respond to T cell receptor stimulation, including reduced expression of cell surface receptor CD69, abolishment of T cell proliferation, and decreased expression of T lymphokines after stimulation by either anti-CD3 plus anti-CD28 or phorbol-12-myristate-13-acetate and ionomycin. Differentiation of Th1 and Th2 CD4+ effector lymphocytes by T cell receptor stimulation was blocked in lal?/? mice. The ratio of CD4+CD25+FoxP3+ Tregs to CD4+ T cells was increased in lal?/? spleens. Bone marrow chimeras demonstrated retardation of T cell development and maturation in lal?/? mice due to defects in T cell precursors. Therefore, LAL, its downstream genes, and lipid mediators all play essential roles in development, homeostasis, and function of T cells. The altered development and function of lal?/? T cells contributes to disease formation in various organs during LAL deficiency.

Qu, Peng; Du, Hong; Wilkes, David S.; Yan, Cong

2009-01-01

55

Differential effects of growth hormone and prolactin on murine T cell development and function.  

PubMed

DW/J dwarf mice have a defect in their anterior pituitary and are deficient in growth hormone (GH) and prolactin (PRL). These mice have been demonstrated previously to have a deficiency in CD4/CD8 double-positive thymocytes, which could be corrected by treatment of these mice with recombinant human GH. Since PRL has been implicated in T cell function and human GH can interact with the PRL receptor, DW/J dwarf mice were treated with either ovine GH (ovGH) (20 micrograms/d) or ovine PRL (ovPRL) (20 micrograms/d). The ovine hormones can only bind their own specific receptors in the mouse. After several weeks of treatment, it was found that these two hormones produced markedly contrasting effects on T cells. Phenotypic analysis of the lymphoid organs was performed by flow cytometry and the functional capability of the peripheral T cells was assessed by immunizing the mice and determining the extent of antigen-specific proliferation of T cells obtained from the draining lymph nodes or by determining splenic mitogen responses. The results indicated that ovGH administration to dwarf mice resulted in significant increases in thymic cellularity yet had little effect on peripheral T cell responses. In contrast, the administration of ovPRL resulted in a further decrease in thymic cellularity when compared with untreated dwarf mice. No thymic effects of either ovGH or ovPRL administration were detected on the normal +/? counterparts. However, ovPRL administration resulted in a significant increase in the number and function of antigen-specific peripheral T cells in both immunized dwarf and +/? mice. The adjuvant effects of PRL occurred even though the mice also received complete Freund's adjuvant. These results suggest that neuroendocrine hormones may act in concert in T cell development. GH appears to promote thymocyte proliferation, while PRL appears to decrease thymus size and yet augment the number and function of antigen-specific T cells in the periphery. PMID:8315380

Murphy, W J; Durum, S K; Longo, D L

1993-07-01

56

Early T cell development and the pitfalls of potential.  

PubMed

The long-standing model for hematopoiesis, which features a dichotomy into separate lymphoid and myeloid branches, predicts that progenitor T cells arise from a lymphocyte-restricted pathway. However, experiments that have detected myeloid potential in progenitor T cells have been reported as evidence to question this model. Mapping physiological differentiation pathways has now led to opposite conclusions, by showing that T cells and thymic myeloid cells have distinct origins and that, in vivo, T cell progenitors lack significant potential for myeloid lineages including dendritic cells. Here, we review the underlying experiments that have led to such fundamentally different conclusions. The current controversy might reflect a need to distinguish between cell fates that are possible experimentally from physiological fate choices, to build a map of immunological differentiation pathways. PMID:20634137

Schlenner, Susan M; Rodewald, Hans-Reimer

2010-08-01

57

Characterization of Normal Human Lung Lymphocytes and Interleukin-2-Induced Lung T Cell Lines.  

National Technical Information Service (NTIS)

Lymphocytes from the lower respiratory tract were obtained by bronchoalveolar lavage of healthy, non-smoking individuals. Various monoclonal antibodies characterizing activated T cells, helper-inducer and suppressor-inducer T cell subsets, and naive versu...

S. Becker D. T. Harris H. S. Koren

1990-01-01

58

Vitamin D receptor expression controls proliferation of na?ve CD8+ T cells and development of CD8 mediated gastrointestinal inflammation  

PubMed Central

Background Vitamin D receptor (VDR) deficiency contributes to the development of experimental inflammatory bowel disease (IBD) in several different models. T cells have been shown to express the VDR, and T cells are targets of vitamin D. In this article we determined the effects of VDR expression on CD8+ T cells. Results VDR KO CD8+ T cells, but not WT CD8+ T cells, induced colitis in Rag KO recipients. In addition, co-transfer of VDR KO CD8+ T cells with naïve CD4+ T cells accelerated colitis development. The more severe colitis was associated with rapidly proliferating naïve VDR KO CD8+ T cells and increased IFN-? and IL-17 in the gut. VDR KO CD8+ T cells proliferated in vitro without antigen stimulation and did not downregulate CD62L and upregulate CD44 markers following proliferation that normally occurred in WT CD8+ T cells. The increased proliferation of VDR KO CD8+ cells was due in part to the higher production and response of the VDR KO cells to IL-2. Conclusions Our data indicate that expression of the VDR is required to prevent replication of quiescent CD8+ T cells. The inability to signal through the VDR resulted in the generation of pathogenic CD8+ T cells from rapidly proliferating cells that contributed to the development of IBD.

2014-01-01

59

Defect in recruiting effector memory CD8+ T-cells in malignant pleural effusions compared to normal pleural fluid  

PubMed Central

Background Malignant pleural effusions (MPE) are a common and fatal complication in cancers including lung or breast cancers, or malignant pleural mesothelioma (MPM). MPE animal models and immunotherapy trials in MPM patients previously suggested defects of the cellular immunity in MPE. However only few observational studies of the immune response were done in MPM patients, using questionable control groups (transudate…). Methods We compared T cell populations evaluated by flow cytometry from blood and pleural effusion of untreated patients with MPM (n?=?58), pleural metastasis of adenocarcinoma (n?=?30) or with benign pleural lesions associated with asbestos exposure (n?=?23). Blood and pleural fluid were also obtained from healthy subjects, providing normal values for T cell populations. Results Blood CD4+ or CD8+ T cells percentages were similar in all groups of patients or healthy subjects. Whereas pleural fluid from healthy controls contained mainly CD8+ T cells, benign or malignant pleural effusions included mainly CD4+ T cells. Effector memory T cells were the main T cell subpopulation in pleural fluid from healthy subjects. In contrast, there was a striking and selective recruitment of central memory CD4+ T cells in MPE, but not of effector cells CD8+ T cells or NK cells in the pleural fluid as one would expect in order to obtain an efficient immune response. Conclusions Comparing for the first time MPE to pleural fluid from healthy subjects, we found a local defect in recruiting effector CD8+ T cells, which may be involved in the escape of tumor cells from immune response. Further studies are needed to characterize which subtypes of effector CD8+ T cells are involved, opening prospects for cell therapy in MPE and MPM.

2013-01-01

60

Altered thymic selection and increased autoimmunity caused by ectopic expression of DRAK2 during T cell development  

PubMed Central

Negative regulation of T cell receptor (TCR) signaling is an important mechanism enforcing immunological self-tolerance to prevent inappropriate activation of T cells and thus the development of autoimmune diseases. The lymphoid-restricted serine/threonine kinase DAP-related apoptotic kinase-2 (DRAK2) raises the TCR activation threshold by targeting TCR-induced calcium mobilization in thymocytes and peripheral T cells, and regulates positive thymic selection and peripheral T cell activation. Despite a hypersensitivity of peripheral drak2-deficient T cells, drak2-deficient mice are enigmatically resistant to induced autoimmunity in the model experimental autoimmune encephalomyelitis (EAE). In order to further evaluate the differential role of DRAK2 in central versus peripheral tolerance and to assess its impact on the development of autoimmune diseases, we have generated a transgenic (Tg) mouse strain ectopically expressing DRAK2 via the lck proximal promoter (1017-DRAK2 Tg mice). This transgene led to highest expression levels in double-positive thymocytes that are normally devoid of DRAK2. 1017-DRAK2 Tg mice displayed a reduction of single-positive CD4+ and CD8+ thymocytes in context with diminished negative selection in male HY TCR × 1017-DRAK2 Tg mice as well as peripheral T cell hypersensitivity, enhanced susceptibility to EAE and spontaneous autoimmunity. These findings suggest that alteration in thymocyte signaling thresholds impacts the sensitivity of peripheral T cell pools.

Gatzka, Martina; Newton, Ryan H.; Walsh, Craig M.

2009-01-01

61

Effect of reduced EPHB4 expression in thymic epithelial cells on thymocyte development and peripheral T cell function.  

PubMed

The Eph kinase (EPH) and ephrin (EFN) families are involved in a broad range of developmental processes. Increasing evidence is demonstrating the important roles of EPHBs and EphrinBs in the immune system. In this study on epithelial cell-specific Ephb4 knockout (KO) mice, we investigated T-cell development and function after EPHB4 deletion. KO mice presented normal thymic weight and cellularity. Their thymocyte subpopulation percentages were in the normal range. KO mice had normal T-cell numbers and percentages in the spleen, and T cells were activated and proliferated normally upon TCR ligation. Furthermore, naïve spleen CD4 cells from KO and wild type mice were capable of differentiating, in a comparable manner, into Th1, Th17 and Treg cells. In vivo, KO mice mounted effective delayed type hypersensitivity responses, indicating that thymocytes develop normally in the absence of TEC EPHB4, and T cells derived from EPHB4-deleted thymic epithelian cells (TEC) have normal function. Our data suggest that heavy redundancy and promiscuous interaction between EPHs and EFNs compensate for the missing EPHB4 in TECs, and TEC EPHB4's role in T cell development might only be revealed if multiple EPHs are ablated simultaneously. We cannot exclude the possibility that (1) some immunological parameters not examined in this study are affected by the deletion; (2) the deletion is not complete due to the leaky Cre-LoxP system, and the remaining EPHB4 in TEC is sufficient for thymocyte development; or (3) EPHB4 expression in TEC is not required for T cell development and function. PMID:24246266

Jin, Wei; Luo, Hongyu; Wu, Jiangping

2014-03-01

62

The signaling suppressor CIS controls proallergic T cell development and allergic airway inflammation.  

PubMed

Transcription factors of the STAT family are critical in the cytokine-mediated functional differentiation of CD4(+) helper T cells. Signaling inhibitors of the SOCS family negatively regulate the activation of STAT proteins; however, their roles in the differentiation and function of helper T cells are not well understood. Here we found that the SOCS protein CIS, which was substantially induced by interleukin 4 (IL-4), negatively regulated the activation of STAT3, STAT5 and STAT6 in T cells. CIS-deficient mice spontaneously developed airway inflammation, and CIS deficiency in T cells led to greater susceptibility to experimental allergic asthma. CIS-deficient T cells showed enhanced differentiation into the TH2 and TH9 subsets of helper T cells. STAT5 and STAT6 regulated IL-9 expression by directly binding to the Il9 promoter. Our data thus demonstrate a critical role for CIS in controlling the proallergic generation of helper T cells. PMID:23727894

Yang, Xuexian O; Zhang, Huiyuan; Kim, Byung-Seok; Niu, Xiaoyin; Peng, Juan; Chen, Yuhong; Kerketta, Romica; Lee, Young-Hee; Chang, Seon Hee; Corry, David B; Wang, Demin; Watowich, Stephanie S; Dong, Chen

2013-07-01

63

Opportunities and challenges in development of phosphoantigens as V?9V?2 T cell agonists.  

PubMed

In contrast to T cells that express the more prevalent ?? T cell receptor and respond to peptide antigens, T cells that express the V?9V?2 T cell receptor detect and respond to non-peptide phosphorous-containing small molecules known as phosphoantigens. Because ?? T cells are early responders to infections and malignancies, it has been suggested that stimulation of their activity with small molecule phosphoantigen drugs may hold promise for therapeutic interventions. Recent studies have greatly advanced our knowledge of phosphoantigens as well as their cellular receptors. At the same time, clinical trials of phosphoantigens have suggested that development of these V?9V?2 T cell agonists has met unexpected challenges. In this commentary, we summarize the biology that underlies phosphoantigen activity and discuss the structural features of synthetic phosphoantigens that affect both their ability to stimulate V?9V?2 T cells and their potential as therapeutic agents. PMID:24680696

Wiemer, David F; Wiemer, Andrew J

2014-06-01

64

Kinetics of T-cell development of umbilical cord blood transplantation in severe T-cell immunodeficiency disorders  

Microsoft Academic Search

Background: Hematopoietic stem-cell transplantation is the treatment of choice for severe primary T-cell immunodeficiencies. When an HLA-identical sibling donor is not available, an alternative donor stem-cell source is needed. In primary T-cell immunodeficiencies, T-cell–depleted HLA-haploidentical bone marrow transplantation has been particularly successful in reconstituting the T-cell immune system in many of the severe combined immunodeficiency syndrome types. However, there are

Alan P. Knutsen; Donna A. Wall

1999-01-01

65

Regulation of early T cell development by the PHD finger of histone lysine methyltransferase ASH1  

SciTech Connect

We have previously isolated a mammalian homologue of Drosophila discsabsent, small, orhomeotic-1 (ash1) from the murine thymus, and recently shown that its SET domain methylates histone H3 lysine 36 (K36). Expression of ASH1 has been reported to be increased in NOD thymocytes in a BDC2.5 clonotype background, but its function in T cell development has remained elusive. Here we report that the ash1 gene is expressed at high levels in thymocytes of mice deficient for rag1 or tcra genes. ASH1 proteins are present at peri-nuclei and as nuclear speckles in thymocytes. Some of the nuclear ASH1 co-localize with RAG2. Expression of the evolutionarily conserved PHD finger of ASH1 impairs T cell development at the DP stage, and causes increased transcription from the HoxA9 promoter in vitro. Moreover, the C-terminal part of ASH1 interacts with HDAC1 repression complexes, suggesting that the PHD finger of ASH1 may be involved in down-regulation of genes for normal development of {alpha}{beta} T cells.

Tanaka, Yujiro [Genome Structure and Expression, School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo 113-8610 (Japan)], E-mail: ytanaka.bgen@mri.tmd.ac.jp; Nakayama, Yasuhiro [Department of Genetics, Yale University School of Medicine, 300 Cedar St., New Haven, CT 06510 (United States); Taniguchi, Masaru [Department of Developmental Immunology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670 (Japan); Kioussis, Dimitris [Department of Molecular Immunology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA (United Kingdom)

2008-01-18

66

Separation of Notch1 Promoted Lineage Commitment and Expansion\\/Transformation in Developing T Cells  

Microsoft Academic Search

Notch1 signaling is required for T cell development. We have previously demonstrated that expression of a dominant active Notch1 (ICN1) transgene in hematopoietic stem cells (HSCs) leads to thymic-independent development of CD4 ? CD8 ? double-positive (DP) T cells in the bone marrow (BM). To understand the function of Notch1 in early stages of T cell develop- ment, we assessed

David Allman; Fredrick G. Karnell; Jennifer A. Punt; Sonia Bakkour; Lanwei Xu; Peggy Myung; Gary A. Koretzky; John C. Pui; Jon C. Aster; Warren S. Pear

67

Innate PLZF+CD4+ ?? T Cells Develop and Expand in the Absence of Itk.  

PubMed

T cell development in the thymus produces multiple lineages of cells, including innate T cells. Studies in mice harboring alterations in TCR signaling proteins or transcriptional regulators have revealed an expanded population of CD4(+) innate T cells in the thymus that produce IL-4 and express the transcription factor promyelocytic leukemia zinc finger (PLZF). In these mice, IL-4 produced by the CD4(+)PLZF(+) T cell population leads to the conversion of conventional CD8(+) thymocytes into innate CD8(+) T cells resembling memory T cells expressing eomesodermin. The expression of PLZF, the signature invariant NKT cell transcription factor, in these innate CD4(+) T cells suggests that they might be a subset of ?? or ?? TCR(+) NKT cells or mucosal-associated invariant T (MAIT) cells. To address these possibilities, we characterized the CD4(+)PLZF(+) innate T cells in itk(-/-) mice. We show that itk(-/-) innate PLZF(+)CD4(+) T cells are not CD1d-dependent NKT cells, MR1-dependent MAIT cells, or ?? T cells. Furthermore, although the itk(-/-) innate PLZF(+)CD4(+) T cells express ?? TCRs, neither ?2-microglobulin-dependent MHC class I nor any MHC class II molecules are required for their development. In contrast to invariant NKT cells and MAIT cells, this population has a highly diverse TCR?-chain repertoire. Analysis of peripheral tissues indicates that itk(-/-) innate PLZF(+)CD4(+) T cells preferentially home to spleen and mesenteric lymph nodes owing to increased expression of gut-homing receptors, and that their expansion is regulated by commensal gut flora. These data support the conclusion that itk(-/-) innate PLZF(+)CD4(+) T cells are a novel subset of innate T cells. PMID:24928994

Prince, Amanda L; Watkin, Levi B; Yin, Catherine C; Selin, Liisa K; Kang, Joonsoo; Schwartzberg, Pamela L; Berg, Leslie J

2014-07-15

68

Flow cytometric analysis of the stimulatory response of T cell subsets from normal and HIV-1+ individuals to various mitogenic stimuli in vitro.  

PubMed Central

A novel technique is described which allows the study of the responses of T cell subpopulations stimulated in bulk cultures without interfering with cell-cell interactions. The number and phenotype of lymphoblasts developing following stimulation with phytohaemagglutinin (PHA), anti-CD3, staphylococcal protein A (SPA) and pokeweed mitogen (PWM) was determined in HIV-1- and HIV-1+ patients using a new five-parameter flow cytometric method. We found that normal T cells responded faster to PHA than to any of the other mitogens tested. The peak of the PHA response occurred on day 3, followed by anti-CD3 and SPA on day 4 and PWM mitogen on day 5. Although PHA and anti-CD3 stimulated up to 95% and 80% of lymphocytes, respectively, SPA and PWM stimulated only 40% and 30% of cells, respectively. A defective T cell response was observed in lymphocytes cultured from asymptomatic HIV-1+ patients compared with negative controls. This loss of response was related to a selective mortality of T cells following mitogenic stimulation, referred to as activation-associated lymphocyte death (AALD). The results showed that stronger mitogens (PHA and anti-CD3) induced AALD in a larger proportion (50-60%) of T cells than weaker mitogens such as SPA and PWM (30-40%), and that AALD affected different lymphocyte subsets to different extents. AALD occurred more frequently in total CD8+ and CD45RO+ T cells compared with CD4+ and CD45RA+ T cells, but memory CD4+ T cells were the population most severely affected in samples from HIV-1+ donors.

Medina, E; Borthwick, N; Johnson, M A; Miller, S; Bofill, M

1994-01-01

69

Immunogenicity of an aerogenic BCG vaccine in T-cell-depleted and normal mice.  

PubMed Central

Aerogenic infection of adult thymectomized, lethally irradiated, bone marrow-reconstituted (THXB) C57B1 times C3H F1 hybrid mice with 1 to 3,000 viable BCG Montreal was followed by an extended period of logarithmic growth to a maximum population of 5 times 10-6 bacilli by day 35. The infection spread to the liver, spleen, and bone marrow with extensive multiplication in all test organs before the growth curves abruptly entered a stationary phase. Up to 30% of the THXB mice eventually died as a result of the ongoing BCG infection. There was no sign of an antimicrobial immune response in the THXB mice analogous to that seen in the control animals beginning about day 30. The THXB mice developed considerable immediate but no delayed hypersensitivity to PPD. Intravenous challenge of the BCG-vaccinated THXB mice with 105 virulent Mycobacterium tuberculosis Erdman indicated that they were as susceptible to the tuberculous challenge as a group of unvaccinated controls. Visible surface lesions developed on the lung 90 days postinfection in the T-cell-depleted host with a sharp rise in counts to 175 per lobe on day 120 followed by a plateau for the remainder of the study. Control mice developed visible lesions about day 50, with 225 lesions per lobe by day 70 and a sharp decline to undetectable levels by day 90. The histopathology of these changes was examined carefully, together with the rate of cellular proliferation (tritiated thymidine uptake) by lung and spleen cells as the BCG infection progressed in the THXB mice. Peak uptake by both organs was depressed during the early stages of the BCG infection in the T-cell-depleted mice, but later the incorporation rates were significantly elevated above control values as the infection progressed. Images

Morrison, N E; Collins, F M

1975-01-01

70

Interleukin-1 receptors are differentially expressed in normal and psoriatic T cells.  

PubMed

This study was carried out to examine the possible role of interleukin-1 (IL-1) in the functional insufficiency of regulatory T cells in psoriasis, by comparing the expression of IL-1 receptors on healthy control and psoriatic T cells. Patients with moderate-to-severe chronic plaque psoriasis and healthy volunteers, matched in age and sex, were selected for all experiments. CD4(+)CD25(-) effector and CD4(+)CD25(+)CD127(low) regulatory T cells were separated and used for the experiments. Expression of the mRNA of IL-1 receptors (IL-1R1, IL-1R2, and sIL-1R2) was determined by quantitative real-time RT-PCR. Cell surface IL-1 receptor expression was assessed by flow cytometry. Relative expression of the signal transmitting IL-1 receptor type 1 (IL-1R1) mRNA is higher in resting psoriatic effector and regulatory T cells, and activation induces higher IL-1R1 protein expression in psoriatic T cells than in healthy cells. Psoriatic regulatory and effector T cells express increased mRNA levels of the decoy IL-1 receptors (IL-1R2 and sIL-1R2) upon activation compared to healthy counterparts. Psoriatic T cells release slightly more sIL-1R2 into their surrounding than healthy T cells. In conclusion, changes in the expression of IL-1 receptors in psoriatic regulatory and effector T cells could contribute to the pathogenesis of psoriasis. PMID:24665164

Bebes, Attila; Kovács-Sólyom, Ferenc; Prihoda, Judit; Kui, Róbert; Kemény, Lajos; Gyulai, Rolland

2014-01-01

71

Differential Requirement for CCR4 and CCR7 during the Development of Innate and Adaptive ??T Cells in the Adult Thymus  

PubMed Central

??T cell development depends upon serial migration of thymocyte precursors through cortical and medullary microenvironments, enabling specialized stromal cells to provide important signals at specific stages of their development. Although conventional ??T cells are subject to clonal deletion in the medulla, entry into the thymus medulla also fosters ??T cell differentiation. For example, during postnatal periods, the medulla is involved in the intrathymic generation of multiple ??T cell lineages, notably the induction of Foxp3+ regulatory T cell development and the completion of invariant NKT cell development. Although migration of conventional ??T cells to the medulla is mediated by the chemokine receptor CCR7, how other T cell subsets gain access to medullary areas during their normal development is not clear. In this study, we show that combining a panel of thymocyte maturation markers with cell surface analysis of CCR7 and CCR4 identifies distinct stages in the development of multiple ??T cell lineages in the thymus. Although Aire regulates expression of the CCR4 ligands CCL17 and CCL22, we show that CCR4 is dispensable for thymocyte migration and development in the adult thymus, demonstrating defective T cell development in Aire?/? mice is not because of a loss of CCR4-mediated migration. Moreover, we reveal that CCR7 controls the development of invariant NKT cells by enabling their access to IL-15 trans-presentation in the thymic medulla and influences the balance of early and late intrathymic stages of Foxp3+ regulatory T cell development. Collectively, our data identify novel roles for CCR7 during intrathymic T cell development, highlighting its importance in enabling multiple ??T cell lineages to access the thymic medulla.

Cowan, Jennifer E.; McCarthy, Nicholas I.; Parnell, Sonia M.; White, Andrea J.; Bacon, Andrea; Serge, Arnauld; Irla, Magali; Lane, Peter J. L.; Jenkinson, Eric J.; Jenkinson, William E.

2014-01-01

72

Immune or normal gamma delta T cells that assist alpha beta T cells in elicitation of contact sensitivity preferentially use V gamma 5 and V delta 4 variable region gene segments.  

PubMed

In the current study, we confirmed previous findings suggesting that gamma delta T cells were involved in the successful adoptive cell transfer of contact sensitivity (CS) by alpha beta CS-effector T cells. In this study, we used hamster anti-mouse gamma delta-TCR mAb treatment of CS-effector T cells, followed by enrichment and removal of the gamma delta T cells with goat anti-hamster Ig-linked magnetic beads, or by addition of hemolytic rabbit C. This removal of gamma delta T cells abrogated adoptive cell transfers of CS, despite the presence of alpha beta T cells that are known to mediate CS. FACS analysis documented enrichment of gamma delta T cells rising from 1 to 2% of the starting cells, to 60 to 95% of the magnetic bead adherent cells. Adoptive cell transfer of CS was reconstituted by adding back to the alpha beta cells, highly enriched gamma delta cells attached to anti-gamma delta-TCR magnetic beads. Not only were gamma delta-enriched T cells from sensitized mice able to assist immune CS-effector alpha beta T cells, but gamma delta T cells from normal nonimmune mice also had CS-assisting activity, and furthermore, neither were MHC-restricted in this function. Thus, CS-assisting gamma delta T cells were present endogenously in normal mice without prior immunization, and acted without Ag specificity and without MHC restriction, to assist CS-effector alpha beta T cells. Similar studies, with hamster mAbs specific for V gamma and V delta portions of gamma delta-TCR, demonstrated that the gamma delta T cells that assisted the CS-effector alpha beta T cells preferentially expressed V gamma 5 and V delta 4 in their TCR. PCR analysis on extracted mRNA showed that V gamma 5 and V delta 4 gene segments indeed were rearranged and expressed in the sensitized and normal lymph nodes; and one-and two-color FACS analysis of magnetic bead-fractionated cells suggested that V gamma 5 and V delta 4 were expressed on the same T cells. In summary, these results demonstrated that V gamma 5+, V delta 4+, gamma delta T cells were needed to assist alpha beta effector T cells in the adoptive cell transfer of CS. PMID:8558025

Ptak, W; Szczepanik, M; Ramabhadran, R; Askenase, P W

1996-02-01

73

DNA damage-independent apoptosis induced by curcumin in normal resting human T cells and leukaemic Jurkat cells.  

PubMed

Curcumin, a phytochemical derived from the rhizome of Curcuma longa, is a very potent inducer of cancer cell death. It is believed that cancer cells are more sensitive to curcumin treatment than normal cells. Curcumin has been shown to act as a prooxidant and induce DNA lesions in normal cells. We were interested in whether curcumin induces DNA damage and the DNA damage response (DDR) signalling pathway leading to apoptosis in normal resting human T cells. To this end, we analysed DNA damage after curcumin treatment of resting human T cells (CD3(+)) and of proliferating leukaemic Jurkat cells by the fluorimetric detection of alkaline DNA unwinding (FADU) assay and immunocytochemical detection of ?-H2AX foci. We showed that curcumin-treated Jurkat cells and resting T cells showed neither DNA lesions nor did they activate key proteins in the DDR signalling pathway, such as phospho-ATM and phospho-p53. However, both types of cell were equally sensitive to curcumin-induced apoptosis and displayed activation of caspase-8 but not of DNA damage-dependent caspase-2. Altogether, our results revealed that curcumin can induce apoptosis of normal resting human T cells that is not connected with DNA damage. PMID:23486648

Korwek, Zbigniew; Bielak-Zmijewska, Anna; Mosieniak, Grazyna; Alster, Olga; Moreno-Villanueva, Maria; Burkle, Alexander; Sikora, Ewa

2013-07-01

74

A transgenic TCR directs the development of IL-4+ and PLZF+ innate CD4 T cells  

PubMed Central

MHC class II expressing thymocytes can efficiently mediate positive selection of CD4 T cells in mice. Thymocyte selected CD4 (T-CD4) T cells have an innate-like phenotype similar to invariant NKT (iNKT) cells. To investigate the development and function of T-CD4 T cells in depth, we cloned TCR genes from T-CD4 T cells and generated transgenic mice. Remarkably, positive selection of T-CD4 TCR Transgenic (T3) thymocytes occurred more efficiently when MHC class II was expressed by thymocytes than by thymic epithelial cells. Similar to polyclonal T-CD4 T cells and also iNKT cells, T3 CD4 T cell development is controlled by SLAM/SAP signaling and the cells expressed both IL-4 and promyelocytic leukemia zinc finger (PLZF). Surprisingly, the selected T3 CD4 T cells were heterogeneous in that only half expressed IL-4 and only half expressed PLZF. IL-4 and PLZF expressing cells were first found at the double positive cell stage. Thus, the expression of IL-4 and PLZF seems to be determined by an unidentified event that occurs post-selection and is not solely dependent on TCR specificity or the selection process, per se. Together, our data show, for the first time, that the TCR specificity regulates but does not determine the development of innate CD4 T cells by thymocytes.

Zhu, Lingqiao; Qiao, Yu; Choi, Esther S.; Das, Joy; Sant'Angelo, Derek B.; Chang, Cheong-Hee

2013-01-01

75

Essential requirement of an invariant V alpha 14 T cell antigen receptor expression in the development of natural killer T cells.  

PubMed Central

NK1.1+ T [natural killer (NK) T] cells express an invariant T cell antigen receptor alpha chain (TCR alpha) encoded by V alpha 14 and J alpha 281 segments in association with a limited number of V betas, predominantly V beta 8.2. Expression of the invariant V alpha 14/J alpha 281, but not V alpha 1, TCR in transgenic mice lacking endogenous TCR alpha expression blocks the development of conventional T alpha beta cells and leads to the preferential development of V alpha 14 NK T cells, suggesting a prerequisite role of invariant V alpha 14 TCR in NK T cell development. In V beta 8.2 but not B beta 3 transgenic mice, two NK T cells with different CD3 epsilon expressions, CD3 epsilon(dim) and CD3 epsilon(high), can be identified. CD3 epsilon(high) NK T cells express surface V alpha 14/V beta 8 TCR, indicating a mature cell type, whereas CD3 epsilon(dim) NK T cells express V beta 8 without V alpha 14 TCR and no significant CD3 epsilon expression (CD3 epsilon(dim)) on the cell surface. However, the latter are positive for recombination activating gene (RAG-1 and RAG-2) mRNA, which are only expressed in the precursor or immature T cell lineage, and also possess CD3 epsilon mRNA in their cytoplasm, suggesting that CD3 epsilon(dim) NK T cells are the precursor of V alpha 14 NK T cells. Images Fig. 1 Fig. 3 Fig. 4

Taniguchi, M; Koseki, H; Tokuhisa, T; Masuda, K; Sato, H; Kondo, E; Kawano, T; Cui, J; Perkes, A; Koyasu, S; Makino, Y

1996-01-01

76

Stochastic component to development of class I major histocompatibility complex-specific T cells.  

PubMed Central

The mechanism by which an initially uncommitted cell chooses between alternative fates is a central issue in developmental biology. In the mammalian thymus, CD4 helper T cells and CD8 cytotoxic T cells arise from a common precursor that expresses both CD4 and CD8. The choice between the CD4 and CD8 lineage is linked to the specificity of the T-cell antigen receptor expressed by a thymocyte, but whether lineage commitment is stochastic or instructed has not been definitively resolved. We present evidence that expression of a constitutive CD8 transgene during thymic selection permits development of mature CD4 cells bearing the class I-restricted F5 T-cell antigen receptor. These results suggest that there is a stochastic component to the development of class I major histocompatibility complex-restricted T cells.

Itano, A; Kioussis, D; Robey, E

1994-01-01

77

Specificity for the tumor-associated self-antigen WT1 drives the development of fully functional memory T cells in the absence of vaccination.  

PubMed

Recently, vaccines against the Wilms Tumor antigen 1 (WT1) have been tested in cancer patients. However, it is currently not known whether physiologic levels of WT1 expression in stem and progenitor cells of normal tissue result in the deletion or tolerance induction of WT1-specific T cells. Here, we used an human leukocyte antigen-transgenic murine model to study the fate of human leukocyte antigen class-I restricted, WT1-specific T cells in the thymus and in the periphery. Thymocytes expressing a WT1-specific T-cell receptor derived from high avidity human CD8 T cells were positively selected into the single-positive CD8 population. In the periphery, T cells specific for the WT1 antigen differentiated into CD44-high memory phenotype cells, whereas T cells specific for a non-self-viral antigen retained a CD44(low) naive phenotype. Only the WT1-specific T cells, but not the virus-specific T cells, displayed rapid antigen-specific effector function without prior vaccination. Despite long-term persistence of WT1-specific memory T cells, the animals did not develop autoimmunity, and the function of hematopoietic stem and progenitor cells was unimpaired. This is the first demonstration that specificity for a tumor-associated self-antigen may drive differentiation of functionally competent memory T cells. PMID:21447831

Pospori, Constandina; Xue, Shao-An; Holler, Angelika; Voisine, Cecile; Perro, Mario; King, Judith; Fallah-Arani, Farnaz; Flutter, Barry; Chakraverty, Ronjon; Stauss, Hans J; Morris, Emma C

2011-06-23

78

Normal T-cell response and in vivo magnetic resonance imaging of T cells loaded with HIV transactivator-peptide-derived superparamagnetic nanoparticles  

Microsoft Academic Search

The present study analyzed the feasibility of using magnetic resonance imaging (MRI) to monitor T-cell homing in vivo after loading T cells with superparamagnetic iron oxide (CLIO) nanoparticles derivatized with a peptide sequence from the transactivator protein (Tat) of HIV-1. T cells were isolated from C57BL\\/6 (B6) mice and loaded with 0, 400, 800, 1600, or 8000 ng\\/ml of FITC

Christopher H. Dodd; Hui-Chen Hsu; Wen-Jang Chu; Pingar Yang; Huang-Ge Zhang; John D. Mountz Jr; Kurt Zinn; John Forder; Lee Josephson; Ralph Weissleder; James M. Mountz

2001-01-01

79

Rapid Proliferation and Differentiation Impairs the Development of Memory CD8+ T Cells in Early Life.  

PubMed

Neonates often generate incomplete immunity against intracellular pathogens, although the mechanism of this defect is poorly understood. An important question is whether the impaired development of memory CD8(+) T cells in neonates is due to an immature priming environment or lymphocyte-intrinsic defects. In this article, we show that neonatal and adult CD8(+) T cells adopted different fates when responding to equal amounts of stimulation in the same host. Whereas adult CD8(+) T cells differentiated into a heterogeneous pool of effector and memory cells, neonatal CD8(+) T cells preferentially gave rise to short-lived effector cells and exhibited a distinct gene expression profile. Surprisingly, impaired neonatal memory formation was not due to a lack of responsiveness, but instead because neonatal CD8(+) T cells expanded more rapidly than adult cells and quickly became terminally differentiated. Collectively, these findings demonstrate that neonatal CD8(+) T cells exhibit an imbalance in effector and memory CD8(+) T cell differentiation, which impairs the formation of memory CD8(+) T cells in early life. PMID:24850719

Smith, Norah L; Wissink, Erin; Wang, Jocelyn; Pinello, Jennifer F; Davenport, Miles P; Grimson, Andrew; Rudd, Brian D

2014-07-01

80

E2A deficiency leads to abnormalities in alphabeta T-cell development and to rapid development of T-cell lymphomas.  

PubMed Central

The E2A gene products, E12 and E47, are critical for proper early B-cell development and commitment to the B-cell lineage. Here we reveal a new role for E2A in T-lymphocyte development. Loss of E2A activity results in a partial block at the earliest stage of T-lineage development. This early T-cell phenotype precedes the development of a T-cell lymphoma which occurs between 3 and 9 months of age. The thymomas are monoclonal and highly malignant and display a cell surface phenotype similar to that of immature thymocytes. In addition, the thymomas generally express high levels of c-myc. As assayed by comparative genomic hybridization, each of the tumor populations analyzed showed a nonrandom gain of chromosome 15, which contains the c-myc gene. Taken together, the data suggest that the E2A gene products play a role early in thymocyte development that is similar to their function in B-lineage determination. Furthermore, the lack of E2A results in development of T-cell malignancies, and we propose that E2A inactivation is a common feature of a wide variety of human T-cell proliferative disorders, including those involving the E2A heterodimeric partners tal-1 and lyl-1.

Bain, G; Engel, I; Robanus Maandag, E C; te Riele, H P; Voland, J R; Sharp, L L; Chun, J; Huey, B; Pinkel, D; Murre, C

1997-01-01

81

Regulation of Lipid Signaling by Diacylglycerol Kinases during T Cell Development and Function  

PubMed Central

Diacylglycerol (DAG) and phosphatidic acid (PA) are bioactive lipids synthesized when the T cell receptor binds to a cognate peptide-MHC complex. DAG triggers signaling by recruiting Ras guanyl-releasing protein 1, PKC?, and other effectors, whereas PA binds to effector molecules that include mechanistic target of rapamycin, Src homology region 2 domain-containing phosphatase 1, and Raf1. While DAG-mediated pathways have been shown to play vital roles in T cell development and function, the importance of PA-mediated signals remains less clear. The diacylglycerol kinase (DGK) family of enzymes phosphorylates DAG to produce PA, serving as a molecular switch that regulates the relative levels of these critical second messengers. Two DGK isoforms, ? and ?, are predominantly expressed in T lineage cells and play an important role in conventional ?? T cell development. In mature T cells, the activity of these DGK isoforms aids in the maintenance of self-tolerance by preventing T cell hyper-activation and promoting T cell anergy. In this review, we discuss the roles of DAG-mediated pathways, PA-effectors, and DGKs in T cell development and function. We also highlight recent work that has uncovered previously unappreciated roles for DGK activity, for instance in invariant NKT cell development, anti-tumor and anti-viral CD8 responses, and the directional secretion of soluble effectors.

Krishna, Sruti; Zhong, Xiao-Ping

2013-01-01

82

T-cell tolerance to the developing equine conceptus.  

PubMed

One of the most intriguing and dramatic examples of immunological tolerance is displayed by the mammalian foetal-placental unit, which thrives as a semi-allograft in the mother's uterus during pregnancy. The success of the so-called foetal allograft stands in stark contrast to the failure of most tissue and organ grafts to survive without genetic matching of donor and recipient or drastic immunosuppression of the recipient's immune system. Experiments conducted over the past 60 years have revealed multiple mechanisms that enable the conceptus to avoid immunological detection or destruction. Many of these mechanisms are directed towards evading immune-mediated damage by maternal T lymphocytes, and they can be grouped into three classes: (i) downregulation of major histocompatibility complex (MHC) gene expression in placental trophoblast cells; (ii) local and systemic alterations in maternal immune reactivity; and (iii) innate defence mechanisms of the trophoblast cells that comprise the barrier between foetal and maternal tissues. The redundancy in these protective mechanisms helps ensure the transmission of life from generation to generation and provides a rich field of study of ways in which functional immunological tolerance can be manifest. The variation in placental forms and function among mammalian species present opportunities to discover and understand novel tolerogenic mechanisms that may have broad application in biology, medicine and animal husbandry. This review focuses on the evidence obtained from studies of pregnancy in the mare that support the case for selective T-cell tolerance to the mammalian conceptus. PMID:22827395

Antczak, D F

2012-08-01

83

Chlamydia trachomatis infection alters the development of memory CD8+ T cells.  

PubMed

The obligate intracellular bacterium Chlamydia trachomatis is the most common cause of bacterial sexually transmitted disease in the United States and the leading cause of preventable blindness worldwide. Prior exposure to C. trachomatis has been shown to provide incomplete protection against subsequent infection. One possible explanation for the limited immunity afforded by prior C. trachomatis infection is poor activation of Chlamydia-specific memory CD8+ T cells. In this study, we examined the development of CD8+ memory T cell responses specific for the Chlamydia Ag CrpA. The percentage of CrpA63-71-specific T cells expressing an effector memory T cell phenotype (IL-7R+ CD62low) was dramatically diminished in mice immunized with C. trachomatis, compared with mice immunized with vaccinia virus expressing the CrpA protein. These alterations in memory T cell development were correlated with a significant reduction in the capacity of convalescent mice to mount an enhanced recall response to Chlamydia Ags, compared with the primary response. CrpA-specific memory T cells primed during VacCrpA infection also failed to respond to a challenge with Chlamydia. We therefore investigated whether C. trachomatis infection might have a global inhibitory effect on CD8+ T cell activation by coinfecting mice with C. trachomatis and Listeria monocytogenes and we found that the activation of Listeria-specific naive and memory CD8+ T cells was reduced in the presence of C. trachomatis. Together, these results suggest that Chlamydia is able to alter the development of CD8+ T cell responses during both primary and secondary infection, perhaps accounting for the incomplete protection provided by prior Chlamydia infection. PMID:16951365

Loomis, Wendy P; Starnbach, Michael N

2006-09-15

84

Signalling through TEC kinases regulates conventional versus innate CD8+ T-cell development  

Microsoft Academic Search

Recent data from three laboratories have identified the TEC kinases, ITK and RLK, as crucial regulators of CD8+ T-cell development into the conventional lymphocyte lineage. In the absence of ITK and RLK, CD4+CD8+ thymocytes upregulate the T-box transcription factor eomesodermin, and develop into mature CD8+ T cells that resemble memory cells, exhibit immediate effector cytokine production and depend on IL-15.

Leslie J. Berg

2007-01-01

85

Loss of STAT3 in CD4+ T cells prevents development of experimental autoimmune diseases.  

PubMed

Th17 cells are implicated in CNS autoimmune diseases. We show that mice with targeted-deletion of Stat3 in CD4(+) T cells (CD4(Stat3)(-/-)) do not develop experimental autoimmune uveoretinitis (EAU) or experimental autoimmune encephalomyelitis. Defective Th17 differentiation noted in CD4(Stat3)(-/-) mice is compensated by exaggerated increases in Foxp3-, IL-10-, IL-4-, and IFN-gamma-expressing T cells, suggesting critical roles of STAT3 in shaping Ag-specific CD4(+) T cell repertoire. In mice with EAU, a high percentage of IL-17-expressing T cells in their peripheral lymphoid organs also secrete IFN-gamma while these double-expressors are absent in CD4(Stat3)(-/-) and wild-type mice without EAU, raising the intriguing possibility that uveitis maybe mediated by Th17 and IL-17-expressing Th1 cells. Resistance of Stat3-deficient mice to EAU derives in part from an inability of uveitogenic Th17 and Th1 cells to enter eyes or brain of the CD4(Stat3)(-/-) mouse because of the reduction in the expression of activated alpha4/beta1 integrins on CD4(Stat3)(-/-) T cells. Adoptive transfer of activated interphotoreceptor retinoid-binding protein-specific uveitogenic T cells induced in CD4(Stat3)(-/-) mice a severe EAU characterized by development of retinal folds, infiltration of inflammatory cells into the retina, and destruction of retinal architecture, underscoring our contention that the loss of STAT3 in CD4(+) T cells results in an intrinsic developmental defect that renders CD4(Stat3)(-/-) resistant to CNS inflammatory diseases. STAT3 requirement for IL-17 production by Th17, generation of double positive T cells expressing IL-17 and IFN-gamma, and for T cell trafficking into CNS tissues suggests that STAT3 may be a therapeutic target for modulating uveitis, sceritis, or multiple sclerosis. PMID:18424728

Liu, Xuebin; Lee, Yun Sang; Yu, Cheng-Rong; Egwuagu, Charles E

2008-05-01

86

The Single Positive T Cells Found in CD3-?/??/? Mice Overtly React with Self-Major Histocompatibility Complex Molecules upon Restoration of Normal Surface Density of T Cell Receptor-CD3 Complex  

PubMed Central

CD3-?/?–deficient mice have small thymuses containing cells that show a profound reduction in the surface levels of T cell receptors and terminate their differentiation at the CD4+CD8+ stage. Rather unexpectedly, CD3? or very low single positive T cells accumulate over time in the spleen and lymph nodes of CD3-?/?–deficient mice after a process dependent on MHC expression. Fusion of these peripheral T cells with a CD3-?–positive derivative of the BW5147 TCR-??/?? thymoma resulted in hybridomas that do express an heterogeneous set of T cell receptor ?/? dimers at their surface and at density comparable to those found in hybridomas derived from wild-type peripheral T cells. We have investigated the specificities of these T cell receptors using spleen cells from congenic and mutant mouse strains, and showed that the majority of them readily recognized self-MHC class I or class II molecules. These results demonstrate that by increasing the density and/or output of the T cell receptors expressed in peripheral T cells, one can confer them with the capacity to respond to normal density of self-MHC molecules.

Lin, Shih-Yao; Ardouin, Laurence; Gillet, Anne; Malissen, Marie; Malissen, Bernard

1997-01-01

87

The signaling suppressor CIS controls proallergic T cell development and allergic airway inflammation  

PubMed Central

Transcription factors of the STAT (signal transducer and activator of transcription) family are critical in the cytokine-mediated functional differentiation of CD4+ helper T cells. Members of the SOCS (suppressor of cytokine signaling) family negatively regulate the activation of STAT proteins; however, their roles in the differentiation and function of helper T cells are not well understood. Here we found that the SOCS protein CIS, which was substantially induced by interleukin 4 (IL-4), negatively regulated the activation of STAT3, STAT5 and STAT6 in T cells. CIS-deficient mice spontaneously developed airway inflammation, and CIS deficiency in T cells led to greater susceptibility to experimental allergic asthma. CIS-deficient T cells showed enhanced differentiation into the TH2 and TH9 subsets of helper T cells. STAT5 and STAT6 regulated IL-9 expression by direct binding to its gene. Our data thus demonstrate a critical role for CIS in controlling proallergic generation of helper T cells.

Yang, Xuexian O; Zhang, Huiyuan; Kim, Byung-Seok; Niu, Xiaoyin; Peng, Juan; Chen, Yuhong; Kerketta, Romica; Lee, Young-Hee; Chang, Seon Hee; Corry, David B; Wang, Demin; Watowich, Stephanie S; Dong, Chen

2014-01-01

88

Lymphomas can develop from B cells chronically helped by idiotype-specific T cells  

PubMed Central

B cell lymphomas have been associated with chronic infections and autoimmunity. However, most lymphomas develop in the absence of any known chronic antigenic stimulation. B cells process their highly diversified endogenous immunoglobulin and present clonally unique variable-region idiotypic (Id) peptides on their major histocompatibility complex (MHC) class II molecules to Id-specific T cells. We show that B cells chronically helped by Id-specific Th2 cells developed into large B cell lymphomas with cytogenetic DNA aberrations. The lymphomas expressed high amounts of Id, MHC class II, CD80/86, and CD40 and bidirectionally collaborated with Th2 cells. Thus, MHC class II–presented Id peptides may represent a chronic self-antigenic stimulus for T cell–dependent lymphomagenesis. Eventually, B lymphomas grew independent of T cells. Thus, T cells do not only eliminate cancers as currently believed. In fact, Id-specific Th2 cells can induce B lymphomas.

Zangani, Michael M.; Fr?yland, Marianne; Qiu, Gao Yue; Meza-Zepeda, Leonardo A.; Kutok, Jeffery L.; Thompson, Keith M.; Munthe, Ludvig A.; Bogen, Bjarne

2007-01-01

89

Newly developed multiple myeloma in a patient with primary T-cell lymphoma of bone.  

PubMed

Primary non-Hodgkin's lymphoma of bone (PLB) is rare, and generally presents as a single extensive and destructive bone lesion. Histopathologically, most cases present as diffuse large B-cell lymphoma, and T-cell lymphoma is rare. By contrast, multiple myeloma is a disease defined as the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. We report a case of multiple myeloma that developed during treatment of PLB in a type of T-cell. A 48-yr-old man was diagnosed as T-cell PLB, stage IE, 18 months ago. The patient received the chemoradiotherapy and salvage chemotherapy for PLB. However, the lymphoma progressed with generalized bone pain, and laboratory findings showed bicytopenia and acute renal failure. On bone marrow biopsy, the patient was diagnosed as having multiple myeloma newly developed with primary T-cell lymphoma of bone. In spite of chemotherapy, the patient died of renal failure. PMID:18583898

Hwang, Jun-Eul; Cho, Sang-Hee; Kim, Ok-Ki; Shim, Hyun-Jeong; Lee, Se-Ryeon; Ahn, Jae-Sook; Yang, Duk-Hwan; Kim, Yeo-Kyeoung; Lee, Je-Jung; Kim, Hyeoung-Joon; Chung, Ik-Joo

2008-06-01

90

Newly Developed Multiple Myeloma in a Patient with Primary T-Cell Lymphoma of Bone  

PubMed Central

Primary non-Hodgkin's lymphoma of bone (PLB) is rare, and generally presents as a single extensive and destructive bone lesion. Histopathologically, most cases present as diffuse large B-cell lymphoma, and T-cell lymphoma is rare. By contrast, multiple myeloma is a disease defined as the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. We report a case of multiple myeloma that developed during treatment of PLB in a type of T-cell. A 48-yr-old man was diagnosed as T-cell PLB, stage IE, 18 months ago. The patient received the chemoradiotherapy and salvage chemotherapy for PLB. However, the lymphoma progressed with generalized bone pain, and laboratory findings showed bicytopenia and acute renal failure. On bone marrow biopsy, the patient was diagnosed as having multiple myeloma newly developed with primary T-cell lymphoma of bone. In spite of chemotherapy, the patient died of renal failure.

Hwang, Jun-Eul; Cho, Sang-Hee; Kim, Ok-Ki; Shim, Hyun-Jeong; Lee, Se-Ryeon; Ahn, Jae-Sook; Yang, Duk-Hwan; Kim, Yeo-Kyeoung; Lee, Je-Jung; Kim, Hyeoung-Joon

2008-01-01

91

Predominance of “memory” T cells (CD4+, CDw29+) over “naive” T cells (CD4+, CD45R+) in both normal and diseased human skin  

Microsoft Academic Search

Absolute numbers of CD3+ T lymphocytes and their subpopulations were determined and statistically evaluated in the lesional skin of psoriasis, atopic dermatitis, nummular dermatitis, pityriasis rosea, and lichen planus. Skin sections were divided into horizontal layers and the numbers of CD3+ T cells as well as CD4+ inducer and CD8+ suppressor-cytotoxic T-cell subsets were counted. In addition, absolute numbers of

J. D. Bos; C. Hagenaars; P. K. Das; S. R. Krieg; W. J. Voorn; M. L. Kapsenberg

1989-01-01

92

Mechanistic basis of pre–T cell receptor–mediated autonomous signaling critical for thymocyte development  

Microsoft Academic Search

The pre–T cell receptor (TCR) is crucial for early T cell development and is proposed to function in a ligand-independent way. However, the molecular mechanism underlying the autonomous signals remains elusive. Here we show that the pre-TCR complex spontaneously formed oligomers. Specific charged residues in the extracellular domain of the pre-TCR ?-chain mediated formation of the oligomers in vitro. Alteration

Sho Yamasaki; Eri Ishikawa; Machie Sakuma; Koji Ogata; Kumiko Sakata-Sogawa; Michio Hiroshima; David L Wiest; Makio Tokunaga; Takashi Saito

2005-01-01

93

Chlamydia trachomatis Infection Alters the Development of Memory CD8 T Cells1  

Microsoft Academic Search

pared with mice immunized with vaccinia virus expressing the CrpA protein. These alterations in memory T cell development were correlated with a significant reduction in the capacity of convalescent mice to mount an enhanced recall response to Chla- mydia Ags, compared with the primary response. CrpA-specific memory T cells primed during VacCrpA infection also failed to respond to a challenge

Wendy P. Loomis; Michael N. Starnbach

2006-01-01

94

Induction of T Cell Development from Hematopoietic Progenitor Cells by Delta-like-1 In Vitro  

Microsoft Academic Search

The molecular interactions provided by the thymic microenvironment that predicate T cell development remain obscure. Here, we show that a bone marrow stromal cell line ectopically expressing the Notch ligand Delta-like-1 loses its ability to support B cell lymphopoiesis, but acquires the capacity to induce the differentiation of hematopoietic progenitors into CD4 CD8 double- and single-positive T cells. Both ??-TCR+

Thomas M. Schmitt; Juan Carlos Zúñiga-Pflücker

2002-01-01

95

A role for BP-3/BST-1 antigen in early T cell development.  

PubMed

In the mouse thymus, pre-T cells are defined by their CD3(-)CD4(-)CD8(-) triple-negative, CD44lo/- CD25+ phenotype. We made a rat mAb IF-7, that, among all T cell subsets analyzed, reacted exclusively with pre-T cells. Molecular cloning revealed that the antigen recognized by IF-7 was identical to BP-3/BST-1, a glycosyl-phosphatidylinositol-linked, CD38-related molecule previously described as a possible co-activation molecule of pre-B cells. We found that IF-7 cross-linking enhances the proliferative response of sorted pre-T cells to anti-CD3 stimulation. In addition, IF-7 enhances and accelerates the development of fetal thymic organ culture (FTOC), although the gamma delta lineage is unaffected by the treatment. In addition, sorted IF-7+ pre-T cells give preferentially rise to alpha beta TCR+ thymocytes in FTOC. Our observations strongly suggest that BP-3/BST-1 is implicated in both early B and T cell growth and development, and is an early marker for the alpha beta lineage. PMID:8671603

Vicari, A P; Bean, A G; Zlotnik, A

1996-02-01

96

Notch Signaling in T-Cell Development and T-ALL  

PubMed Central

The Notch signaling pathway is an evolutionarily conserved cell signaling system present in most multicellular organisms, as it controls cell fate specification by regulating cell proliferation, differentiation, apoptosis, and survival. Regulation of the Notch signaling pathway can be achieved at multiple levels. Notch proteins are involved in lineage fate decisions in a variety of tissues in various species. Notch is essential for T lineage cell differentiation including T versus B and ?? versus ?? lineage specification. In this paper, we discuss Notch signaling in normal T-cell maturation and differentiation as well as in T-cell acute lymphoblastic lymphoma/leukemia.

Li, Xiaoyu; von Boehmer, Harald

2011-01-01

97

D1 and D2 Dopamine Receptor-mediated Inhibition of Activated Normal T Cell Proliferation Is Lost in Jurkat T Leukemic Cells*  

PubMed Central

Dopamine is a catecholamine neurotransmitter, which plays an important role in the regulation of T cell functions. In activated T cells from normal volunteers, stimulation of D1 and D2 dopamine receptors inhibit cell proliferation and cytokine secretion. However, there is no report yet regarding the regulatory role of D1 and D2 dopamine receptors in abnormally proliferating T cells. The present study investigates the expression and effect of activation of these dopamine receptors in Jurkat cells, a leukemic T cell line showing uncontrolled proliferation. Like normal human T cells, in Jurkat cells, D1 and D2 dopamine receptors are also expressed; however, unlike activated normal T cells, stimulation of these dopamine receptors in Jurkat cells fails to inhibit their T cell receptor-induced proliferation. This alteration is due to failure of D1 dopamine receptor-mediated activation of cyclic AMP signaling and a missense mutation at the third cytoplasmic loop of D2 dopamine receptors affecting inhibition of phosphorylation of ZAP-70, an important downstream protein transducing signal from the T cell receptor. These results help to understand the biology of abnormal proliferation of T cells in pathophysiological conditions where dopamine plays an important role.

Basu, Biswarup; Sarkar, Chandrani; Chakroborty, Debanjan; Ganguly, Subhalakshmi; Shome, Saurav; Dasgupta, Partha Sarathi; Basu, Sujit

2010-01-01

98

The transcription factor PU.1 is required for the development of IL9-producing T cells and allergic inflammation  

Microsoft Academic Search

CD4+ helper T cells acquire effector phenotypes that promote specialized inflammatory responses. We show that the ETS-family transcription factor PU.1 was required for the development of an interleukin 9 (IL-9)-secreting subset of helper T cells. Decreasing PU.1 expression either by conditional deletion in mouse T cells or the use of small interfering RNA in human T cells impaired IL-9 production,

Hua-Chen Chang; Sarita Sehra; Ritobrata Goswami; Weiguo Yao; Qing Yu; Gretta L Stritesky; Rukhsana Jabeen; Carl McKinley; Ayele-Nati Ahyi; Ling Han; Evelyn T Nguyen; Michael J Robertson; Narayanan B Perumal; Robert S Tepper; Stephen L Nutt; Mark H Kaplan

2010-01-01

99

The Ets-1 transcription factor controls the development and function of natural regulatory T cells  

PubMed Central

Regulatory T cells (T reg cells) constitute a population of CD4+ T cells that limits immune responses. The transcription factor Foxp3 is important for determining the development and function of T reg cells; however, the molecular mechanisms that trigger and maintain its expression remain incompletely understood. In this study, we show that mice deficient for the Ets-1 transcription factor (Ets-1?/?) developed T cell–mediated splenomegaly and systemic autoimmunity that can be blocked by functional wild-type T reg cells. Spleens of Ets-1?/? mice contained mostly activated T cells, including Th2-polarized CD4+ cells and had reduced percentages of T reg cells. Splenic and thymic Ets-1?/? T reg cells expressed low levels of Foxp3 and displayed the CD103 marker that characterizes antigen-experienced T reg cells. Thymic development of Ets-1?/? T reg cells appeared intrinsically altered as Foxp3-expressing cells differentiate poorly in mixed fetal liver reconstituted chimera and fetal thymic organ culture. Ets-1?/? T reg cells showed decreased in vitro suppression activity and did not protect Rag2?/? hosts from naive T cell–induced inflammatory bowel disease. Furthermore, in T reg cells, Ets-1 interacted with the Foxp3 intronic enhancer and was required for demethylation of this regulatory sequence. These data demonstrate that Ets-1 is required for the development of natural T reg cells and suggest a role for this transcription factor in the regulation of Foxp3 expression.

Mouly, Enguerran; Chemin, Karine; Nguyen, Hai Vu; Chopin, Martine; Mesnard, Laurent; Leite-de-Moraes, Maria; Burlen-defranoux, Odile; Bandeira, Antonio

2010-01-01

100

The Ets-1 transcription factor controls the development and function of natural regulatory T cells.  

PubMed

Regulatory T cells (T reg cells) constitute a population of CD4(+) T cells that limits immune responses. The transcription factor Foxp3 is important for determining the development and function of T reg cells; however, the molecular mechanisms that trigger and maintain its expression remain incompletely understood. In this study, we show that mice deficient for the Ets-1 transcription factor (Ets-1(-/-)) developed T cell-mediated splenomegaly and systemic autoimmunity that can be blocked by functional wild-type T reg cells. Spleens of Ets-1(-/-) mice contained mostly activated T cells, including Th2-polarized CD4(+) cells and had reduced percentages of T reg cells. Splenic and thymic Ets-1(-/-) T reg cells expressed low levels of Foxp3 and displayed the CD103 marker that characterizes antigen-experienced T reg cells. Thymic development of Ets-1(-/-) T reg cells appeared intrinsically altered as Foxp3-expressing cells differentiate poorly in mixed fetal liver reconstituted chimera and fetal thymic organ culture. Ets-1(-/-) T reg cells showed decreased in vitro suppression activity and did not protect Rag2(-/-) hosts from naive T cell-induced inflammatory bowel disease. Furthermore, in T reg cells, Ets-1 interacted with the Foxp3 intronic enhancer and was required for demethylation of this regulatory sequence. These data demonstrate that Ets-1 is required for the development of natural T reg cells and suggest a role for this transcription factor in the regulation of Foxp3 expression. PMID:20855499

Mouly, Enguerran; Chemin, Karine; Nguyen, Hai Vu; Chopin, Martine; Mesnard, Laurent; Leite-de-Moraes, Maria; Burlen-defranoux, Odile; Bandeira, Antonio; Bories, Jean-Christophe

2010-09-27

101

NKAP, a novel modulator of Notch signaling, is required for T cell development  

PubMed Central

T cell development depends on the coordinated interplay between receptor signaling and transcriptional activation/repression. We performed a genetic complementation screen, and identified a novel transcriptional repressor, NKAP. NKAP associates with HDAC3 and is part of a DNA-binding complex, as shown by chromatin immunoprecipitation. NKAP also associates with CIR, a part of the Notch corepressor complex. The expression of NKAP during T cell development inversely correlates with the expression of Notch target genes, implying that NKAP may modulate Notch-mediated transcription. To examine the function of NKAP in T cell development, Lck-cre NKAP conditional knockout mice were generated. Interestingly, loss of NKAP blocks development of ?? but not ?? T cells. In addition, Lck-cre NKAP cKO DP T cells express 8- to 20-fold higher levels of Hes1, Deltex1 and CD25, providing in vivo evidence that NKAP functions as a transcriptional repressor, acting at least in part, by repression of the Notch pathway.

Pajerowski, Anthony G.; Nguyen, Chau; Aghajanian, Haig; Shapiro, Michael J.; Shapiro, Virginia Smith

2009-01-01

102

TOX is required for development of the CD4 T cell lineage gene program  

PubMed Central

The factors that regulate thymic development of the CD4+ T cell gene program remain poorly defined. The transcriptional regulator ThPOK is a dominant factor in CD4+ T cell development, which functions primarily to repress the CD8 lineage fate. Previously, we showed that nuclear protein TOX is also required for murine CD4+ T cell development. Here we sought to investigate if the requirement for TOX was solely due to a role in ThPOK induction. In apparent support of this proposition, ThPOK upregulation and CD8 lineage repression were compromised in the absence of TOX, and enforced ThPOK expression could restore some CD4 development. However, these “rescued” CD4 cells were defective in many aspects of the CD4+ T cell gene program, including expression of Id2, Foxo1, and endogenous Thpok, among others. Thus, TOX is necessary to establish the CD4+ T cell lineage gene program, independent of its influence on ThPOK expression.

Aliahmad, Parinaz; Kadavallore, Asha; de la Torre, Brian; Kappes, Dietmar; Kaye, Jonathan

2011-01-01

103

Enterocyte Expression of Interleukin 7 Induces Development of ?? T Cells and Peyer's Patches  

PubMed Central

The intestinal mucosa is suggested to support extrathymic T cell development, particularly for T cell receptor (TCR)-?? intraepithelial lymphocytes (IELs). TCR-?? cell development requires interleukin (IL)-7; IL-7?/? or IL-7 receptor?/? mice lack TCR-?? cells. Using the intestinal fatty acid binding protein (iFABP) promoter, we reinstated expression of IL-7 to mature enterocytes of IL-7?/? mice (iFABP-IL7). In iFABP-IL7 mice, TCR-?? IELs were restored, as were cryptopatches and Peyer's patches. TCR-?? cells remained absent from all other tissues. Likewise, T cell development in thymus and B cell maturation in the bone marrow and spleen retained the IL-7?/? phenotype. Thus, IL-7 expression by enterocytes was sufficient for extrathymic development of TCR-?? cells in situ within the intestinal epithelium and was crucial for organization of mucosal lymphoid tissue.

Laky, Karen; Lefrancois, Leo; Lingenheld, Elizabeth G.; Ishikawa, Hiromichi; Lewis, Julia M.; Olson, Sara; Suzuki, Kenji; Tigelaar, Robert E.; Puddington, Lynn

2000-01-01

104

SAP-Dependent and -Independent Regulation of Innate T Cell Development Involving SLAMF Receptors.  

PubMed

Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) plays an essential role in the immune system mediating the function of several members of the SLAM family (SLAMF) of receptors, whose expression is essential for T, NK, and B-cell responses. Additionally, the expression of SAP in double-positive thymocytes is mandatory for natural killer T (NKT) cells and, in mouse, for innate CD8(+) T cell development. To date, only two members of the SLAMF of receptors, Slamf1 and Slamf6, have been shown to positively cooperate during NKT cell differentiation in mouse. However, it is less clear whether other members of this family may also participate in the development of these innate T cells. Here, we show that Slamf[1?+?6](-/-) and Slamf[1?+?5?+?6](-/-) B6 mice have ~70% reduction of NKT cells compared to wild-type B6 mice. Unexpectedly, the proportion of innate CD8(+) T cells slightly increased in the Slamf[1?+?5?+?6](-/-) , but not in the Slamf[1?+?6](-/-) strain, suggesting that Slamf5 may function as a negative regulator of innate CD8(+) T cell development. Accordingly, Slamf5(-/-) B6 mice showed an exclusive expansion of innate CD8(+) T cells, but not NKT cells. Interestingly, the SAP-independent Slamf7(-/-) strain showed an expansion of both splenic innate CD8(+) T cells and thymic NKT cells. On the other hand, and similar to what was recently shown in Slamf3(-/-) BALB/c mice, the proportions of thymic promyelocytic leukemia zinc finger (PLZF(hi)) NKT cells and innate CD8(+) T cells significantly increased in the SAP-independent Slamf8(-/-) BALB/c strain. In summary, these results show that NKT and innate CD8(+) T cell development can be regulated in a SAP-dependent and -independent fashion by SLAMF receptors, in which Slamf1, Slamf6, and Slamf8 affect development of NKT cells, and that Slamf5, Slamf7, and Slamf8 affect the development of innate CD8(+) T cells. PMID:24795728

De Calisto, Jaime; Wang, Ninghai; Wang, Guoxing; Yigit, Burcu; Engel, Pablo; Terhorst, Cox

2014-01-01

105

SAP-Dependent and -Independent Regulation of Innate T Cell Development Involving SLAMF Receptors  

PubMed Central

Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) plays an essential role in the immune system mediating the function of several members of the SLAM family (SLAMF) of receptors, whose expression is essential for T, NK, and B-cell responses. Additionally, the expression of SAP in double-positive thymocytes is mandatory for natural killer T (NKT) cells and, in mouse, for innate CD8+ T cell development. To date, only two members of the SLAMF of receptors, Slamf1 and Slamf6, have been shown to positively cooperate during NKT cell differentiation in mouse. However, it is less clear whether other members of this family may also participate in the development of these innate T cells. Here, we show that Slamf[1?+?6]?/? and Slamf[1?+?5?+?6]?/?B6 mice have ~70% reduction of NKT cells compared to wild-type B6 mice. Unexpectedly, the proportion of innate CD8+ T cells slightly increased in the Slamf[1?+?5?+?6]?/?, but not in the Slamf[1?+?6]?/? strain, suggesting that Slamf5 may function as a negative regulator of innate CD8+ T cell development. Accordingly, Slamf5?/? B6 mice showed an exclusive expansion of innate CD8+ T cells, but not NKT cells. Interestingly, the SAP-independent Slamf7?/? strain showed an expansion of both splenic innate CD8+ T cells and thymic NKT cells. On the other hand, and similar to what was recently shown in Slamf3?/? BALB/c mice, the proportions of thymic promyelocytic leukemia zinc finger (PLZFhi) NKT cells and innate CD8+ T cells significantly increased in the SAP-independent Slamf8?/? BALB/c strain. In summary, these results show that NKT and innate CD8+ T cell development can be regulated in a SAP-dependent and -independent fashion by SLAMF receptors, in which Slamf1, Slamf6, and Slamf8 affect development of NKT cells, and that Slamf5, Slamf7, and Slamf8 affect the development of innate CD8+ T cells.

De Calisto, Jaime; Wang, Ninghai; Wang, Guoxing; Yigit, Burcu; Engel, Pablo; Terhorst, Cox

2014-01-01

106

Histamine type I (H/sub 1/) receptor radioligand binding studies on normal T cell subsets, B cells, and monocytes  

SciTech Connect

A single, specific binding site for (/sup 3/H)pyrilamine on normal human T helper, T suppressor, B cells, and monocytes was documented. The binding of the radioligand to its receptor is reversible with cold H/sub 1/ antagonist, saturates at 40 to 60 nM, and binding equilibrium is achieved in 2 to 4 min. Using a computer program (Ligand), the authors calculated the dissociation constants, binding capacities, and numbers of receptors per cell for each of the different cell types. Monocytes were found to have the highest affinity for (/sup 3/H)pyrilamine, followed by T helper cells, B cells and T suppressor cells (K/sub D/ = 44.6 +/- 49.4 nM). T suppressor cells were found to express the higher number of H/sub 1/ receptors per cell followed by B cells, T helper cells, and monocytes. The binding affinity for (/sup 3/H)pyrilamine increased over a 48-hr period, whereas the number of receptors per T cell was essentially unchanged. In contrast, T cells stimulated with Con A or PHA were shown to have a greater than fourfold increase in the number of receptors per cell, whereas the binding affinity for (/sup 3/H)pyrilamine decreased over the 48-hr period. Although the function of H/sub 1/ receptors on T cells, B cells, and monocytes has not been completely defined, this receptor has the potential of playing an important role in the modulating the immune response.

Cameron, W.; Doyle, K.; Rocklin, R.E.

1986-03-15

107

Engineered regulatory T cells coexpressing MHC class II:peptide complexes are efficient inhibitors of autoimmune T cell function and prevent the development of autoimmune arthritis.  

PubMed

Regulatory T cells (Tregs) are critical homeostatic components in preventing the development of autoimmunity, and are a major focus for their therapeutic potential for autoimmune diseases. To enhance the efficacy of Tregs in adoptive therapy, we developed a strategy for generating engineered Tregs that have the capacity to target autoimmune T cells in an Ag-specific manner. Using a retroviral expression system encoding Foxp3 and HLA-DR1 covalently linked to the immunodominant peptide of the autoantigen type II collagen (DR1-CII), naive T cells were engineered to become Tregs that express DR1-CII complexes on their surface. When these cells were tested for their ability to prevent the development of collagen induced arthritis, both the engineered DR1-CII-Foxp3 and Foxp3 only Tregs significantly reduced the severity and incidence of disease. However, the mechanism by which these two populations of Tregs inhibited disease differed significantly. Disease inhibition by the DR1-CII-Foxp3 Tregs was accompanied by significantly lower numbers of autoimmune CII-specific T cells in vivo and lower levels of autoantibodies in comparison with engineered Tregs expressing Foxp3 alone. In addition, the numbers of IFN-?- and IL-17-expressing T cells in mice treated with DR1-CII-Foxp3 Tregs were also significantly reduced in comparison with mice treated with Foxp3 engineered Tregs or vector control cells. These data indicate that the coexpression of class II autoantigen-peptide complexes on Tregs provides these cells with a distinct capacity to regulate autoimmune T cell responses that differs from that used by conventional Tregs. PMID:23630354

Qian, Zhaohui; Latham, Kary A; Whittington, Karen B; Miller, David C; Brand, David D; Rosloniec, Edward F

2013-06-01

108

A 10-aa-long sequence in SLP-76 upstream of the Gads binding site is essential for T cell development and function  

PubMed Central

The adapter SLP-76 is essential for T cell development and function. SLP-76 binds to the src homology 3 domain of Lck in vitro. This interaction depends on amino acids 185–194 of SLP-76. To examine the role of the Lck-binding region of SLP-76 in T cell development and function, SLP-76-/- mice were reconstituted with an SLP-76 mutant that lacks amino acids 185–194. Double and single positive thymocytes from reconstituted mice were severely reduced in numbers and exhibited impaired positive selection and increased apoptosis. Peripheral T cells were also reduced in numbers, exhibited impaired phospholipase C-?1 and Erk phosphorylation, and failed to flux calcium, secrete IL-2, and proliferate in response to T cell antigen receptor ligation. Delayed cutaneous hypersensitivity responses and Ab responses to T cell-dependent antigen were severely impaired. These results indicate that the Lck binding region of SLP-76 is essential for T cell antigen receptor signaling and normal T cell development and function.

Kumar, Lalit; Feske, Stefan; Rao, Anjana; Geha, Raif S.

2005-01-01

109

T Cell Development and T Cell Responses in Mice with Mutations Affecting Tyrosines 292 or 315 of the Zap-70 Protein Tyrosine Kinase  

PubMed Central

After stimulation of the T cell receptor (TCR), the tyrosine residues 292 and 315 in interdomain B of the protein tyrosine kinase ZAP-70 become phosphorylated and plausibly function as docking sites for Cbl and Vav1, respectively. The two latter proteins have been suggested to serve as substrates for ZAP-70 and to fine-tune its function. To address the role of these residues in T cell development and in the function of primary T cells, we have generated mice that express ZAP-70 molecules with Tyr to Phe substitution at position 292 (Y292F) or 315 (Y315F). When analyzed in a sensitized TCR transgenic background, the ZAP-70 Y315F mutation reduced the rate of positive selection and delayed the occurrence of negative selection. Furthermore, this mutation unexpectedly affected the constitutive levels of the CD3-? p21 phosphoisoform. Conversely, the ZAP-70 Y292F mutation upregulated proximal events in TCR signaling and allowed more T cells to produce interleukin 2 and interferon ? in response to a given dose of antigen. The observation that ZAP-70 Y292F T cells have a slower rate of ligand-induced TCR downmodulation suggests that Y292 is likely involved in regulating the duration activated TCR reside at the cell surface. Furthermore, we showed that Y292 and Y315 are dispensable for the TCR-induced tyrosine phosphorylation of Cbl and Vav1, respectively. Therefore, other molecules present in the TCR signaling cassette act as additional adaptors for Cbl and Vav1. The present in vivo analyses extend previous data based on transformed T cell lines and suggest that residue Y292 plays a role in attenuation of TCR signaling, whereas residue Y315 enhances ZAP-70 function.

Magnan, Antoine; Di Bartolo, Vincenzo; Mura, Anne-Marie; Boyer, Claude; Richelme, Mireille; Lin, Yea-Lih; Roure, Agnes; Gillet, Anne; Arrieumerlou, Cecile; Acuto, Oreste; Malissen, Bernard; Malissen, Marie

2001-01-01

110

Role of the IL7 Receptor in ?? T-Cell Development from Hematopoietic Stem Cells  

Microsoft Academic Search

\\u000a Interleukin 7 (IL-7) is an essential cytokine for early lymphocyte development. The IL-7 receptor (IL-7R) transmits at least\\u000a two signals in lymphocyte progenitors. One is for survival and proliferation of early and mature lymphocytes. The other is\\u000a to promote V(D)J recombination of the immunoglobulin heavy (IgH) and T-cell receptor ? (TCR?) loci. ?? T cells with a specific\\u000a variable (V)

Koichi Ikuta; Shizue Tani-ichi

111

Dietary restriction and fasting arrest B and T cell development and increase mature B and T cell numbers in bone marrow.  

PubMed

Dietary restriction (DR) delays ageing and extends life span. Both long- and short-term DR, as well as short-term fasting provide robust protection against many "neuronal and surgery related damaging phenomena" such as Parkinson's disease and ischemia-reperfusion injury. The exact mechanism behind this phenomenon has not yet been elucidated. Its anti-inflammatory actions prompted us to thoroughly investigate the consequences of DR and fasting on B and T cell compartments in primary and secondary lymphoid organs of male C57Bl/6 mice. In BM we found that DR and fasting cause a decrease in the total B cell population and arrest early B cell development, while increasing the number of recirculating mature B cells. In the fasting group, a significant reduction in peripheral B cell counts was observed in both spleen and mesenteric lymph nodes (mLN). Thymopoiesis was arrested significantly at double negative DN2 stage due to fasting, whereas DR resulted in a partial arrest of thymocyte development at the DN4 stage. Mature CD3(+) T cell populations were increased in BM and decreased in both spleen and mLN. Thus, DR arrests B cell development in the BM but increases the number of recirculating mature B cells. DR also arrests maturation of T cells in thymus, resulting in depletion of mature T cells from spleen and mLN while recruiting them to the BM. The functional relevance in relation to protection against organ damage needs to be determined. PMID:24504160

Shushimita, Shushimita; de Bruijn, Marjolein J W; de Bruin, Ron W F; IJzermans, Jan N M; Hendriks, Rudi W; Dor, Frank J M F

2014-01-01

112

Kinetics of T-cell receptor-dependent antigen recognition determined in vivo by multi-spectral normalized epifluorescence laser scanning  

NASA Astrophysics Data System (ADS)

Detection of multiple fluorophores in conditions of low signal represents a limiting factor for the application of in vivo optical imaging techniques in immunology where fluorescent labels report for different functional characteristics. A noninvasive in vivo Multi-Spectral Normalized Epifluorescence Laser scanning (M-SNELS) method was developed for the simultaneous and quantitative detection of multiple fluorophores in low signal to noise ratios and used to follow T-cell activation and clonal expansion. Colocalized DsRed- and GFP-labeled T cells were followed in tandem during the mounting of an immune response. Spectral unmixing was used to distinguish the overlapping fluorescent emissions representative of the two distinct cell populations and longitudinal data reported the discrete pattern of antigen-driven proliferation. Retrieved values were validated both in vitro and in vivo with flow cytometry and significant correlation between all methodologies was achieved. Noninvasive M-SNELS successfully quantified two colocalized fluorescent populations and provides a valid alternative imaging approach to traditional invasive methods for detecting T cell dynamics.

Favicchio, Rosy; Zacharakis, Giannis; Oikonomaki, Katerina; Zacharopoulos, Athanasios; Mamalaki, Clio; Ripoll, Jorge

2012-07-01

113

Differential G-protein expression during B- and T-cell development.  

PubMed Central

The molecular mechanisms underlying B- and T-cell development are, as yet, poorly understood. However, as G proteins regulate a diverse range of biological responses including growth, proliferation and differentiation, we have investigated differential expression of G proteins during B- and T-cell development with the aim of identifying key signals involved in lymphocyte maturation. Differential expression of beta 1/2 and alpha-subunits of the Gs-, i- and q-families was found throughout lymphoid development. Most strikingly, G alpha i1 and G alpha i1 were very weakly, or not expressed in pre-, immature and mature B cells, thymocytes or mature T cells, but strongly induced in mature B-lymphoblastoid cell lines, some of which have been used as models of germinal centre B cells, suggesting that expression of these G proteins may correlate with the later stages of B-cell development. In contrast, G alpha 16 expression was highest in T cells and pre-B cells and progressively declined with B-cell maturation. These findings suggest that G proteins, and the signals they regulate, such as ion channels and/or adenylate cyclase (G alpha s/i) and phospholipase C (G beta gamma and G alpha 11/16) are differentially regulated in lymphoid cells in a maturation-and lineage-dependent manner. Images Figure 1

Grant, K R; Harnett, W; Milligan, G; Harnett, M M

1997-01-01

114

Rapamycin Reduces Disease Activity and Normalizes T Cell Activation-Induced Calcium Fluxing in Patients With Systemic Lupus Erythematosus  

PubMed Central

Objective Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown origin. Current treatment options are often ineffective or poorly tolerated. Recent observations have revealed mitochondrial hyperpolarization and enhanced Ca2+ fluxing in T cells from SLE patients. Rapamycin, a lipophilic macrolide antibiotic that regulates mitochondrial transmembrane potential and Ca2+ fluxing, has been used safely and effectively to treat renal transplant rejection since 1999. In addition, rapamycin has been shown to ameliorate T cell function and to prolong survival in lupus-prone MRL/lpr mice. We therefore undertook the present study to investigate whether rapamycin is beneficial in patients with SLE. Methods Nine patients with clinically active SLE that had been treated unsuccessfully with other immunosuppressive medications began therapy with rapamycin, 2 mg/day orally. Disease activity was assessed with the British Isles Lupus Assessment Group (BILAG) score, SLE Disease Activity Index (SLEDAI), and requirement for prednisone therapy. Mitochondrial transmembrane potential and Ca2+ fluxing were assessed by flow cytometry. Results In patients treated with rapamycin, the BILAG score was reduced by a mean ± SEM of 1.93 ± 0.9 (P = 0.0218), the SLEDAI by 5.3 ± 0.8 (P = 0.00002), and concurrent prednisone use by 26.4 ± 6.7 mg/day (P = 0.0062) compared with pre–rapamycin treatment. While mitochondrial hyperpolarization persisted, pretreatment cytosolic and mitochondrial Ca2+ levels and T cell activation–induced rapid Ca2+ fluxing were normalized in rapamycin-treated patients. Conclusion Rapamycin appears to be a safe and effective therapy for SLE that has been refractory to traditional medications. Mitochondrial dysfunction and Ca2+ fluxing could serve as biomarkers to guide decisions regarding future therapeutic interventions in SLE.

Fernandez, David; Bonilla, Eduardo; Mirza, Naureen; Niland, Brian; Perl, Andras

2014-01-01

115

Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene.  

PubMed Central

To determine which CD3 components are required for early T cell development, we generated mice with a targeted mutation of the CD3-epsilon gene and characterized their T cell populations relative to those found in CD3-zeta/eta-and recombinase activating gene (RAG)-deficient mice. In the absence of intact CD3-epsilon subunit, thymocytes do not progress beyond the CD44-/lowCD25+ triple-negative stage and appear to be arrested at the very same developmental control point as RAG-deficient thymocytes. In contrast, the disruption of the CD3-epsilon/eta gene does not totally abrogate the progression through this control point. CD3-epsilon-deficient thymocytes do rearrange their T cell receptor (TCR) beta gene segments and produce low levels of full-length TCR beta transcripts. Taken together, these results establish an essential role for the CD3-epsilon gene products during T cell development and further suggest that the CD3-epsilon polypeptides start to exert their function as part of a pre-TCR through which CD44-/lowCD25+ triple-negative cells monitor the occurrence of productive TCR beta gene rearrangements. Finally, the absence of intact CD3-epsilon polypeptides had no discernible effect on the completion of TCR gamma and TCR delta gene rearrangements, emphasizing that they are probably not subjected to the same epigenetic controls as those operating on the expression of TCR alpha and beta genes. Images

Malissen, M; Gillet, A; Ardouin, L; Bouvier, G; Trucy, J; Ferrier, P; Vivier, E; Malissen, B

1995-01-01

116

Bioinformatic Description of Immunotherapy Targets for Pediatric T-Cell Leukemia and the Impact of Normal Gene Sets Used for Comparison  

PubMed Central

Pediatric lymphoid leukemia has the highest cure rate of all pediatric malignancies, yet due to its prevalence, still accounts for the majority of childhood cancer deaths and requires long-term highly toxic therapy. The ability to target B-cell ALL with immunoglobulin-like binders, whether anti-CD22 antibody or anti-CD19 CAR-Ts, has impacted treatment options for some patients. The development of new ways to target B-cell antigens continues at rapid pace. T-cell ALL accounts for up to 20% of childhood leukemia but has yet to see a set of high-value immunotherapeutic targets identified. To find new targets for T-ALL immunotherapy, we employed a bioinformatic comparison to broad normal tissue arrays, hematopoietic stem cells (HSC), and mature lymphocytes, then filtered the results for transcripts encoding plasma membrane proteins. T-ALL bears a core T-cell signature and transcripts encoding TCR/CD3 components and canonical markers of T-cell development predominate, especially when comparison was made to normal tissue or HSC. However, when comparison to mature lymphocytes was also undertaken, we identified two antigens that may drive, or be associated with leukemogenesis; TALLA-1 and hedgehog interacting protein. In addition, TCR subfamilies, CD1, activation and adhesion markers, membrane-organizing molecules, and receptors linked to metabolism and inflammation were also identified. Of these, only CD52, CD37, and CD98 are currently being targeted clinically. This work provides a set of targets to be considered for future development of immunotherapies for T-ALL.

Orentas, Rimas J.; Nordlund, Jessica; He, Jianbin; Sindiri, Sivasish; Mackall, Crystal; Fry, Terry J.; Khan, Javed

2014-01-01

117

Dietary Zinc Deficiency in Rodents: Effects on T-Cell Development, Maturation and Phenotypes  

PubMed Central

Zinc deficiency is one of the leading risk factors for developing disease and yet we do not have a clear understanding of the mechanisms behind the increased susceptibility to infection. This review will examine the interrelationships among the hypothalamus-pituitary-adrenal stress axis, p56lck, and T-cell maturation in both zinc deficiency and responses during zinc repletion. We will highlight differences between the adult mouse model (wasting malnutrition) and growing rat model (stunting malnutrition) of dietary zinc deficiency and discuss the use of various controls to separate out the effects of zinc deficiency from the associated malnutrition. Elevated serum corticosterone in both zinc deficient and pair-fed rats does not support the hypothesis that zinc deficiency per se leads to corticosterone-induced apoptosis and lymphopenia. In fact, the zinc deficient rat does not have lymphopenia. Thymocytes from zinc deficient mice and rats have elevated levels of p56lck, a signalling protein with a zinc clasp structure, but this does not appear to affect thymocyte maturation. However, post-thymic T-cell maturation appears to be altered based on the lower proportion of splenic late thymic emigrants in zinc deficient rats. Fewer new T-cells in the periphery could adversely affect the T-cell repertoire and contribute to immunodeficiency in zinc deficiency.

Blewett, Heather J.; Taylor, Carla G.

2012-01-01

118

Identification of Human T Cell Antigens for the Development of Vaccines Against Mycobacterium Tuberculosis  

PubMed Central

Development of a subunit vaccine for Mycobacterium tuberculosis (Mtb) depends on the identification of antigens that induce appropriate T cell responses. Using bioinformatics, we selected a panel of 94 Mtb genes based on criteria which included growth in macrophages, up- or down-regulation under hypoxic conditions, secretion, membrane association, or because they were members of the PE/PPE or EsX families. Recombinant proteins encoded by these genes were evaluated for IFN-? recall responses using PBMC from healthy subjects previously exposed to Mtb. From this screen, dominant human T-cell antigens were identified and 49 of these proteins, formulated in CpG, were evaluated as vaccine candidates in a mouse model of tuberculosis (TB). Eighteen of the individual antigens conferred partial protection against challenge with virulent Mtb. A combination of three of these antigens further increased protection against Mtb to levels comparable to those achieved with BCG vaccination. Vaccine candidates that led to reduction in lung bacterial burden following challenge induced pluripotent CD4 and CD8 T cells, including TH1 cell responses characterized by elevated levels of antigen-specific IgG2c, IFN-? and TNF. Priority vaccine antigens elicited pluripotent CD4 and CD8 T responses in PPD+ donor PBMC. This study identified numerous novel human T cell antigens suitable to be included in subunit vaccines against TB.

Bertholet, Sylvie; Ireton, Gregory C; Kahn, Maria; Guderian, Jeffrey; Mohamath, Raodoh; Stride, Nicole; Laughlin, Elsa M.; Baldwin, Susan L.; Vedvick, Thomas S.; Coler, Rhea N.; Reed, Steven G.

2008-01-01

119

Design and development of therapies using chimeric antigen receptor-expressing T cells.  

PubMed

Investigators developed chimeric antigen receptors (CARs) for expression on T cells more than 25 years ago. When the CAR is derived from an antibody, the resultant cell should combine the desirable targeting features of an antibody (e.g. lack of requirement for major histocompatibility complex recognition, ability to recognize non-protein antigens) with the persistence, trafficking, and effector functions of a T cell. This article describes how the past two decades have seen a crescendo of research which has now begun to translate these potential benefits into effective treatments for patients with cancer. We describe the basic design of CARs, describe how antigenic targets are selected, and the initial clinical experience with CAR-T cells. Our review then describes our own and other investigators' work aimed at improving the function of CARs and reviews the clinical studies in hematological and solid malignancies that are beginning to exploit these approaches. Finally, we show the value of adding additional engineering features to CAR-T cells, irrespective of their target, to render them better suited to function in the tumor environment, and discuss how the safety of these heavily modified cells may be maintained. PMID:24329793

Dotti, Gianpietro; Gottschalk, Stephen; Savoldo, Barbara; Brenner, Malcolm K

2014-01-01

120

SAP is required for the development of innate phenotype in H2-M3-restricted CD8+ T cells1  

PubMed Central

H2-M3-restricted T cells have a pre-activated surface phenotype, rapidly expand and produce cytokines upon stimulation and as such, are classified as innate T cells. Unlike most innate T cells, M3-restricted T cells also express CD8?? co-receptors and a diverse TCR repertoire: hallmarks of conventional MHC Ia-restricted CD8+ T cells. Although iNKT cells are also innate lymphocytes, they are selected exclusively on hematopoietic cells (HC), while M3-restricted T cells can be selected on either hematopoietic or thymic epithelial cells (TEC). Moreover, their phenotypes differ depending on what cells mediate their selection. Though there is a clear correlation between selection on HC and development of innate phenotype, the underlying mechanism remains unclear. SAP is required for the development of iNKT cells and mediates signals from SLAM receptors that are exclusively expressed on HC. Based on their dual selection pathway, M3-restricted T cells present a unique model for studying the development of innate T cell phenotype. Using both polyclonal and transgenic mouse models we demonstrate that while M3-restricted T cells are capable of developing in the absence of SAP, SAP is required for HC-mediated selection, development of pre-activated phenotype and heightened effector functions of M3-restricted T cells. These findings are significant because they directly demonstrate the need for SAP in HC-mediated acquisition of innate T cell phenotype and suggest that due to their SAP-dependent HC-mediated selection, M3-restricted T cells develop a pre-activated phenotype and an intrinsic ability to proliferate faster upon stimulation, allowing for an important role in the early response to infection.

Bediako, Yaw; Bian, Yao; Zhang, Hong; Cho, Hoonsik; Stein, Paul L.; Wang, Chyung-Ru

2012-01-01

121

T Cell Memory  

Microsoft Academic Search

T cell memory induced by prior infection or vaccination provides enhanced protection against subsequent microbial infections.\\u000a The processes involved in generating and maintaining T cell memory are becoming better understood due to recent technological\\u000a advances in identifying memory T cells and monitoring their behavior and function in vivo. Memory T cells develop in response\\u000a to a progressive set of cues—starting

J. Tan; C. Surh

122

Development of Innate CD4+ and CD8+ T Cells in Itk-Deficient Mice Is Regulated by Distinct Pathways.  

PubMed

T cell development in the thymus produces multiple lineages of cells, including innate T cells such as ?? TCR(+) cells, invariant NKT cells, mucosal-associated invariant T cells, and H2-M3-specific cells. Although innate cells are generally a minor subset of thymocytes, in several strains of mice harboring mutations in T cell signaling proteins or transcriptional regulators, conventional CD8(+) T cells develop as innate cells with characteristics of memory T cells. Thus, in Itk-deficient mice, mature CD4(-)CD8(+) (CD8 single-positive [SP]) thymocytes express high levels of the transcription factor eomesodermin (Eomes) and are dependent on IL-4 being produced in the thymic environment by a poorly characterized subset of CD4(+) thymocytes expressing the transcriptional regulator promyelocytic leukemia zinc finger. In this study, we show that a sizeable proportion of mature CD4(+)CD8(-) (CD4SP) thymocytes in itk(-/-) mice also develop as innate Eomes-expressing T cells. These cells are dependent on MHC class II and IL-4 signaling for their development, indicating that they are conventional CD4(+) T cells that have been converted to an innate phenotype. Surprisingly, neither CD4SP nor CD8SP innate Eomes(+) thymocytes in itk(-/-) or SLP-76(Y145F) mice are dependent on ?? T cells for their development. Instead, we find that the predominant population of Eomes(+) innate itk(-/-) CD4SP thymocytes is largely absent in mice lacking CD1d-specific invariant NKT cells, with no effect on innate itk(-/-) CD8SP thymocytes. In contrast, both subsets of innate Eomes(+)itk(-/-) T cells require the presence of a novel promyelocytic leukemia zinc finger-expressing, SLAM family receptor adapter protein-dependent thymocyte population that is essential for the conversion of conventional CD4(+) and CD8(+) T cells into innate T cells with a memory phenotype. PMID:24943215

Prince, Amanda L; Kraus, Zachary; Carty, Shannon A; Ng, Caleb; Yin, Catherine C; Jordan, Martha S; Schwartzberg, Pamela L; Berg, Leslie J

2014-07-15

123

Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development.  

PubMed

Generation of CD8(+) memory T cells requires metabolic reprogramming that is characterized by enhanced mitochondrial fatty-acid oxidation (FAO). However, where the fatty acids (FA) that fuel this process come from remains unclear. While CD8(+) memory T cells engage FAO to a greater extent, we found that they acquired substantially fewer long-chain FA from their external environment than CD8(+) effector T (Teff) cells. Rather than using extracellular FA directly, memory T cells used extracellular glucose to support FAO and oxidative phosphorylation (OXPHOS), suggesting that lipids must be synthesized to generate the substrates needed for FAO. We have demonstrated that memory T cells rely on cell intrinsic expression of the lysosomal hydrolase LAL (lysosomal acid lipase) to mobilize FA for FAO and memory T cell development. Our observations link LAL to metabolic reprogramming in lymphocytes and show that cell intrinsic lipolysis is deterministic for memory T cell fate. PMID:25001241

O'Sullivan, David; van der Windt, Gerritje J W; Huang, Stanley Ching-Cheng; Curtis, Jonathan D; Chang, Chih-Hao; Buck, Michael D; Qiu, Jing; Smith, Amber M; Lam, Wing Y; DiPlato, Lisa M; Hsu, Fong-Fu; Birnbaum, Morris J; Pearce, Edward J; Pearce, Erika L

2014-07-17

124

506 Basal T Cell Subpopulations of Normal Humans Vary by Stress Hormone Receptor Polymorphisms  

PubMed Central

Background Psychological stress has been correlated with allergy and asthma activity although there are clearly individual differences in the responses to the same stressor. These individual differences could be influenced by stress hormone receptor binding affinity, which could be altered by single nucleotide polymorphisms (SNPs). Methods We categorized differences in immunoregulatory profiles from peripheral blood mononuclear cells (PBMC) of 207 normal volunteers according to various glucocorticoid (GCR) and beta-2 adrenergic receptor (B2AR) polymorphisms. Subjects were genotyped for SNPs by real time RT-PCR, and Th1, Th2, Th1/Th2 ratio, and CD3+CD4+CD25hiFoxp3+ cell numbers were measured using flow cytometry. Each immune parameter in the SNP groups was compared to the wild-type (WT) gene. Results Significant differences were observed in B2AR SNPs Gly16Arg for Th2 (means: WT gly/gly, 1.89; arg/arg, 2.58; P = 0.003) and Th1/Th2 ratio (medians: WT gly/gly, 10.18; arg/arg, 6.89; P = 0.004) and Gln27Glu for Th1 (means: WT gln/gln, 17.21; gln/glu, 19.4 P = 0.031; glu/glu, 19.82 P = 0.049). No differences were observed based upon GCR SNPs tested (BCL1; NC363S; TTh1111; A3669G). Conclusions These data suggest that SNPs from various components of the stress-immune network (such as hormone and cytokine promoters and receptors) may be useful for subgrouping of immune responses to more accurately evaluate psychoneuroimmunological components of stress risk in individual subjects. This approach has significant clinical potentials in identifying those patients who may be most susceptible to stress effects on their immune balance.

Rehm, Kristina; Xiang, Lianbin; Marshall, Gailen

2012-01-01

125

Development of Augmented Leukemia/Lymphoma-Specific T-Cell Immunotherapy for Deployment with Haploidentical, Hematompoietic Progenitor- Cell Transplant.  

National Technical Information Service (NTIS)

To develop T-cell therapies for B-cell malignancies we have developed a chimeric antigen receptor (CAR) which when expressed on the cell surface redirects T-cell specificity for CD19, a B-lineage cell-surface antigen. We have undertaken a series of system...

L. Cooper R. Young

2008-01-01

126

Intrathymic IL-7: The where, when, and why of IL-7 signaling during T cell development  

PubMed Central

The thymus is the birthplace of all T lineage cells. But the thymus is also a cradle as it provides the environment for further maturation and differentiation of immature thymocytes. While many factors contribute to make the thymus a unique place for T cell development, here we review the essential role of intrathymic interleukin-7 (IL-7). In the absence of IL-7 signaling, survival, proliferation and differentiation of immature thymocytes are all severely impaired. Consequently, IL-7 is critical to nurture and guide T precursor cells through the diverse steps of thymic maturation. Interestingly, even as IL-7 signaling is such a critical factor, IL-7 signaling must be also actively suppressed during specific stages of T cell differentiation. These contradictory observations are puzzling but can be satisfactorily explained when understanding the developmental context of IL-7 signaling. In this regard, here we will discuss the spatiotemporal expression of intrathymic IL-7 and address the stage-specific effects of IL-7 signaling in developing thymocytes. Specifically, we will review other facets of intrathymic IL-7 beyond its role as a pro-survival factor and so clarify and reaffirm the unique role of IL-7 as a prime factor in T cell development and differentiation.

Hong, Changwan; Luckey, Megan; Park, Jung-Hyun

2012-01-01

127

Autoimmune gastritis mediated by CD4+ T cells promotes the development of gastric cancer  

PubMed Central

Chronic inflammation is a major risk factor for cancer, including gastric cancers and other gastrointestinal cancers. For example, chronic inflammation caused by autoimmune gastritis (AIG) is associated with an increased risk of gastric polyps, gastric carcinoid tumors, and possibly adenocarcinomas. In this study, we characterized the progression of gastric cancer in a novel mouse model of AIG. In this model, disease was caused by CD4+ T cells expressing a transgenic T cell receptor specific for a peptide from the H+/K+ ATPase proton pump, a protein expressed by parietal cells in the stomach. AIG caused epithelial cell aberrations that mimicked most of those seen in progression of human gastric cancers, including chronic gastritis followed by oxyntic atrophy, mucous neck cell hyperplasia, spasmolytic polypeptide-expressing metaplasia (SPEM), dysplasia and ultimately gastric intraepithelial neoplasias (GIN). Our work provides the first direct evidence that AIG supports the development of gastric neoplasia, and provides a useful model to study how inflammation drives gastric cancer.

Nguyen, Thanh-Long M.; Khurana, Shradha S.; Bellone, Clifford J.; Capoccia, Benjamin J.; Sagartz, John E.; Kesman, Russell A.; Mills, Jason C.; DiPaolo, Richard J.

2013-01-01

128

Development and validation of a canine T-cell-dependent antibody response model for immunotoxicity evaluation.  

PubMed

A T-cell dependent antibody response (TDAR) model to evaluate compounds for potential immunotoxicity in dogs has not been reported. The objective of these studies was to develop and validate a dog TDAR model using the T-cell dependent antigen, keyhole limpet hemocyanin (KLH). Studies were conducted to determine the appropriate dose of KLH, immunization route and kinetics of the antibody response to KLH in the dog. To validate the sensitivity of this method, we investigated the TDAR to KLH in the dog with a known immunosuppressive drug, cyclosporine (Neoral). The results of this study demonstrate that a robust primary IgM and IgG response to KLH can be generated in dogs and the IgG response was sensitive to cyclosporine treatment. PMID:18958674

Finco-Kent, Deborah; Kawabata, Thomas T

2005-10-01

129

Development of T cell lymphoma in HTLV-1 bZIP factor and Tax double transgenic mice.  

PubMed

Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). ATL cells possess a CD4+ CD25+ phenotype, similar to that of regulatory T cells (Tregs). Tax has been reported to play a crucial role in the leukemogenesis of HTLV-1. The HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of the viral genomic RNA, is expressed in all ATL cases and induces neoplastic and inflammatory disease in vivo. To test whether HBZ and Tax are both required for T cell malignancy, we generated HBZ/Tax double transgenic mice in which HBZ and Tax are expressed exclusively in CD4+ T cells. Survival was much reduced in HBZ/Tax double-transgenic mice compared with wild type littermates. Transgenic expression of HBZ and Tax induced skin lesions and T-cell lymphoma in mice, resembling diseases observed in HTLV-1 infected individuals. However, Tax single transgenic mice did not develop major health problems. In addition, memory CD4+ T cells and Foxp3+ Treg cells counts were increased in HBZ/Tax double transgenic mice, and their proliferation was enhanced. There was very little difference between HBZ single and HBZ/Tax double transgenic mice. Taken together, these results show that HBZ, in addition to Tax, plays a critical role in T-cell lymphoma arising from HTLV-1 infection. PMID:24818712

Zhao, Tiejun; Satou, Yorifumi; Matsuoka, Masao

2014-07-01

130

Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts  

PubMed Central

Adoptive transfer of large numbers of tumor-reactive CD8+ cytotoxic T lymphocytes (CTLs) expanded and differentiated in vitro has shown promising clinical activity against cancer. However, such protocols are complicated by extensive ex vivo manipulations of tumor-reactive cells and have largely focused on CD8+ CTLs, with much less emphasis on the role and contribution of CD4+ T cells. Using a mouse model of advanced melanoma, we found that transfer of small numbers of naive tumor-reactive CD4+ T cells into lymphopenic recipients induces substantial T cell expansion, differentiation, and regression of large established tumors without the need for in vitro manipulation. Surprisingly, CD4+ T cells developed cytotoxic activity, and tumor rejection was dependent on class II–restricted recognition of tumors by tumor-reactive CD4+ T cells. Furthermore, blockade of the coinhibitory receptor CTL-associated antigen 4 (CTLA-4) on the transferred CD4+ T cells resulted in greater expansion of effector T cells, diminished accumulation of tumor-reactive regulatory T cells, and superior antitumor activity capable of inducing regression of spontaneous mouse melanoma. These findings suggest a novel potential therapeutic role for cytotoxic CD4+ T cells and CTLA-4 blockade in cancer immunotherapy, and demonstrate the potential advantages of differentiating tumor-reactive CD4+ cells in vivo over current protocols favoring in vitro expansion and differentiation.

Quezada, Sergio A.; Simpson, Tyler R.; Peggs, Karl S.; Merghoub, Taha; Vider, Jelena; Fan, Xiaozhou; Blasberg, Ronald; Yagita, Hideo; Muranski, Pawel; Antony, Paul A.; Restifo, Nicholas P.

2010-01-01

131

T cell development in mice lacking the CD3-zeta/eta gene.  

PubMed Central

The CD3-zeta and CD3-eta polypeptides are two of the components of the T cell antigen receptor (TCR) which contribute to its efficient cell surface expression and account for part of its transducing capability. CD3-zeta and CD3-eta result from the alternative splicing of a single gene designated CD3-zeta/eta. To evaluate the role of these subunits during T cell development, we have produced mice with a disrupted CD3-zeta/eta gene. The analysis of thymocyte populations from the CD3-zeta/eta-/- homozygous mutant mice revealed that they have a profound reduction in the surface levels of TCR complexes and that the products of the CD3-zeta/eta gene appear to be needed for the efficient generation and/or survival of CD4+CD8+ thymocytes. Despite the almost total absence of mature single positive thymocytes, the lymph nodes from zeta/eta-/- mice were found to contain unusual CD4+CD8- and CD4-CD8+ single positive cells which were CD3-. In contrast to the situation observed in the thymus, the thymus-independent gut intraepithelial lymphocytes present in zeta/eta-/- mice do express TCR complexes on their surface and these are associated with Fc epsilon RI gamma homodimers. These results establish an essential role for the CD3-zeta/eta gene products during intrathymic T cell differentiation and further emphasize the difference between conventional T cells and thymus-independent gut intraepithelial lymphocytes. Images

Malissen, M; Gillet, A; Rocha, B; Trucy, J; Vivier, E; Boyer, C; Kontgen, F; Brun, N; Mazza, G; Spanopoulou, E

1993-01-01

132

Control of early stages in invariant natural killer T-cell development  

PubMed Central

Natural killer T (NKT) cells develop in the thymus from the same precursors as conventional CD4+ and CD8+?? T cells, CD4+ CD8+ double-positive cells. In contrast to conventional ??T cells, which are selected by MHC–peptide complexes presented by thymic epithelial cells, invariant NKT cells are selected by lipid antigens presented by the non-polymorphic, MHC I-like molecule CD1d, present on the surface of other double-positive thymocytes, and require additional signals from the signalling lymphocytic–activation molecule (SLAM) family of receptors. In this review, we provide a discussion of recent findings that have modified our understanding of the NKT cell developmental programme, with an emphasis on events that affect the early stages of this process. This includes factors that control double-positive thymocyte lifespan, and therefore the ability to generate the canonical V? rearrangements that characterize this lineage, as well as the signal transduction pathways engaged downstream of the T-cell receptor and SLAM molecules.

Hu, Taishan; Gimferrer, Idoia; Alberola-Ila, Jose

2011-01-01

133

Notch dimerization is required for leukemogenesis and T-cell development  

PubMed Central

Notch signaling regulates myriad cellular functions by activating transcription, yet how Notch selectively activates different transcriptional targets is poorly understood. The core Notch transcriptional activation complex can bind DNA as a monomer, but it can also dimerize on DNA-binding sites that are properly oriented and spaced. However, the significance of Notch dimerization is unknown. Here, we show that dimeric Notch transcriptional complexes are required for T-cell maturation and leukemic transformation but are dispensable for T-cell fate specification from a multipotential precursor. The varying requirements for Notch dimerization result from the differential sensitivity of specific Notch target genes. In particular, c-Myc and pre-T-cell antigen receptor ? (Ptcra) are dimerization-dependent targets, whereas Hey1 and CD25 are not. These findings identify functionally important differences in the responsiveness among Notch target genes attributable to the formation of higher-order complexes. Consequently, it may be possible to develop a new class of Notch inhibitors that selectively block outcomes that depend on Notch dimerization (e.g., leukemogenesis).

Liu, Hudan; Chi, Anthony W.S.; Arnett, Kelly L.; Chiang, Mark Y.; Xu, Lanwei; Shestova, Olga; Wang, Hongfang; Li, Yue-Ming; Bhandoola, Avinash; Aster, Jon C.; Blacklow, Stephen C.; Pear, Warren S.

2010-01-01

134

Epidermal T Cells and Wound Healing  

PubMed Central

The murine epidermis contains resident T cells that express a canonical ?? TCR. These cells arise from fetal thymic precursors and use a TCR that is restricted to the skin in adult animals. These cells assume a dendritic morphology in normal skin and constitutively produce low levels of cytokines that contribute to epidermal homeostasis. When skin is wounded, an unknown antigen is expressed on damaged keratinocytes. Neighboring ?? T cells then round up and contribute to wound healing by local production of epithelial growth factors and inflammatory cytokines. In the absence of skin ?? T cells, wound healing is impaired. Similarly, epidermal T cells from patients with healing wounds are activated and secreting growth factors. Patients with non-healing wounds have a defective epidermal T cell response. Information gained on the role of epidermal-resident T cells in the mouse may provide information for development of new therapeutic approaches to wound healing.

Havran, Wendy L.; Jameson, Julie M.

2010-01-01

135

Dynamic Transcription of Long Non-Coding RNA Genes during CD4+ T Cell Development and Activation  

PubMed Central

Background Recent evidence shows that long non-coding RNA (LncRNA) play important regulatory roles in many biology process, including cell development, activation and oncogenesis. However, the roles of these LncRNAs in the development and activation of CD4+ T cells, which is an important component of immune response, remain unknown. Results To predict the function of LncRNA in the development and activation of CD4+ T cells, first, we examined the expression profiles of LncRNAs and mRNAs in CD4?CD8? (DN), CD4+CD8+ (DP), CD4+CD8?, and activated CD4+CD8? T cells in a microarray analysis and verified these results by real time PCRs (qPCR). We found that the expression of hundreds of LncRNAs significantly changed in each process of developmental transition, including DN into DP, DP into CD4+CD8?, and CD4+CD8? into activated CD4+ T cells. A Kendall distance analysis suggested that the expression of LncRNAs in DN, DP, CD4+CD8? T cells and activated CD4+ T cells were correlated with the expression of mRNAs in these T cells. The Blat algorithm and GO analysis suggested that LncRNAs may exert important roles in the development and activation of CD4+ T cells. These roles included proliferation, homeostasis, maturation, activation, migration, apoptosis and calcium ion transportation. Conclusion The present study found that the expression profiles of LncRNAs in different stages of CD4+ T cells are distinguishable. LncRNAs are involved in the key biological process in CD4+ T cell development and activation.

Yang, Yi; Huang, Anfei; Chen, Si; Sun, Di; Xiong, Sidong; Zhang, Jinping

2014-01-01

136

PD-L1 regulates the development, maintenance, and function of induced regulatory T cells  

PubMed Central

Both the programmed death (PD) 1–PD-ligand (PD-L) pathway and regulatory T (T reg) cells are instrumental to the maintenance of peripheral tolerance. We demonstrate that PD-L1 has a pivotal role in regulating induced T reg (iT reg) cell development and sustaining iT reg cell function. PD-L1?/? antigen-presenting cells minimally convert naive CD4 T cells to iT reg cells, showing the essential role of PD-L1 for iT reg cell induction. PD-L1–coated beads induce iT reg cells in vitro, indicating that PD-L1 itself regulates iT reg cell development. Furthermore, PD-L1 enhances and sustains Foxp3 expression and the suppressive function of iT reg cells. The obligatory role for PD-L1 in controlling iT reg cell development and function in vivo is illustrated by a marked reduction in iT reg cell conversion and rapid onset of a fatal inflammatory phenotype in PD-L1?/?PD-L2?/? Rag?/? recipients of naive CD4 T cells. PD-L1 iT reg cell development is mediated through the down-regulation of phospho-Akt, mTOR, S6, and ERK2 and concomitant with the up-regulation of PTEN, all key signaling molecules which are critical for iT reg cell development. Thus, PD-L1 can inhibit T cell responses by promoting both the induction and maintenance of iT reg cells. These studies define a novel mechanism for iT reg cell development and function, as well as a new strategy for controlling T reg cell plasticity.

Francisco, Loise M.; Salinas, Victor H.; Brown, Keturah E.; Vanguri, Vijay K.; Freeman, Gordon J.; Kuchroo, Vijay K.

2009-01-01

137

Cutting edge: the Foxp3 target miR-155 contributes to the development of regulatory T cells.  

PubMed

Foxp3 is a transcription factor that is essential for the normal development of regulatory T cells (Tregs). In the absence of microRNAs (miRNAs), Foxp3(+) Tregs develop but fail to maintain immune homeostasis, leading to a scurfy-like disease. Global analysis of the network of genes regulated by Foxp3 has identified the miRNA miR-155, which is highly expressed in Tregs, as a direct target of Foxp3. In this study we report that miR-155-deficient mice have reduced numbers of Tregs, both in the thymus and periphery, due to impaired development. However, we found no evidence for defective suppressor activity of miR-155-deficient Tregs, either in vitro or in vivo. Our results indicate that miR-155 contributes to Treg development, but that additional miRNAs control Treg function. PMID:19234151

Kohlhaas, Susan; Garden, Oliver A; Scudamore, Cheryl; Turner, Martin; Okkenhaug, Klaus; Vigorito, Elena

2009-03-01

138

Development of immunoglobulin M memory to both a T-cell-independent and a T-cell-dependent antigen following infection with Vibrio cholerae O1 in Bangladesh.  

PubMed

Vibrio cholerae O1 can cause severe watery diarrhea that can be life-threatening without treatment. Infection results in long-lasting protection against subsequent disease. Development of memory B cells of the immunoglobulin G (IgG) and IgA isotypes to V. cholerae O1 antigens, including serotype-specific lipopolysaccharide (LPS) and the B subunit of cholera toxin (CTB), after cholera infection has been demonstrated. Memory B cells of the IgM isotype may play a role in long-term protection, particularly against T-cell-independent antigens, but IgM memory has not been studied in V. cholerae O1 infection. Therefore, we assayed acute- and convalescent-phase blood samples from cholera patients for the presence of memory B cells that produce cholera antigen-specific IgM antibody upon polyclonal stimulation in in vitro culture. We also examined the development of serological and antibody-secreting cell responses following infection. Subjects developed significant IgM memory responses by day 30 after infection, both to the T-cell-independent antigen LPS and to the T-cell-dependent antigen CTB. No significant corresponding elevations in plasma IgM antibodies or circulating IgM antibody-secreting cells to CTB were detected. In 17 subjects followed to day 90 after infection, significant persistence of elevated IgM memory responses was not observed. The IgM memory response to CTB was negatively correlated with the IgG plasma antibody response to CTB, and there was a trend toward negative correlation between the IgM memory and IgA plasma antibody responses to LPS. We did not observe an association between the IgM memory response to LPS and the vibriocidal titer. PMID:19858296

Kendall, Emily A; Tarique, Abdullah A; Hossain, Azim; Alam, Mohammad Murshid; Arifuzzaman, Mohammad; Akhtar, Nayeema; Chowdhury, Fahima; Khan, Ashraful I; Larocque, Regina C; Harris, Jason B; Ryan, Edward T; Qadri, Firdausi; Calderwood, Stephen B

2010-01-01

139

?-catenin/TCF-1 pathway in T cell development and differentiation  

PubMed Central

T cells must undergo two critical differentiation processes before they become competent effectors that can mediate actual immune responses. Progenitor T cells undergo defined stages of differentiation in the thymus, which include positive and negative selection, to generate a repertoire of T cells that will respond to foreign but not self antigens. When these immunocompetent T cells first migrate out of thymus into peripheral lymphoid tissues, they are naïve and are unable to mediate immune responses. However, upon antigen encounter, peripheral CD4+ naïve T cells undergo another differentiation process to become armed effector T cells including Th1, Th2, Th17 or regulatory T cells, all of which are capable of regulating immune responses. A canonical Wnt/?-catenin/T cell factor (TCF) pathway has been shown to regulate T cell differentiation in both the thymus and in peripheral lymphoid tissues. Dysfunction of this pathway at any stage of T cell differentiation could lead to severe autoimmunity including experimental autoimmune encephalomyelitis or immune deficiency. Understanding the role played by ?-catenin/TCF-1 in T cell differentiation will facilitate our understanding of the mechanisms that regulate T cell function and assist in identifying novel therapy targets for treating both autoimmune and immune diseases. Therefore, in this review, we will focus on the function of ?-catenin/TCF-1 pathway in the regulation of thymic and peripheral T cell differentiation processes.

Ma, Jian; Wang, Ruiqing; Fang, Xianfeng; Sun, Zuoming

2013-01-01

140

Protein dimerization between Lmo2 (Rbtn2) and Tal1 alters thymocyte development and potentiates T cell tumorigenesis in transgenic mice.  

PubMed Central

The LMO2 and TAL1 genes were first identified via chromosomal translocations and later found to encode proteins that interact during normal erythroid development. Some T cell leukaemia patients have chromosomal abnormalities involving both genes, implying that LMO2 and TAL1 act synergistically to promote tumorigenesis after their inappropriate co-expression. To test this hypothesis, transgenic mice were made which co-express Lmo2 and Tal1 genes in T cells. Dimers of Lmo2 and Tal1 proteins were formed in thymocytes of double but not single transgenic mice. Furthermore, thymuses of double transgenic mice were almost completely populated by immature T cells from birth, and these mice develop T cell tumours approximately 3 months earlier than those with only the Lmo2 transgene. Thus interaction between these two proteins can alter T cell development and potentiate tumorigenesis. The data also provide formal proof that TAL1 is an oncogene, apparently acting as a tumour promoter in this system. Images

Larson, R C; Lavenir, I; Larson, T A; Baer, R; Warren, A J; Wadman, I; Nottage, K; Rabbitts, T H

1996-01-01

141

Early Growth Response Gene-2 (Egr-2) Regulates the Development of B and T Cells  

PubMed Central

Background Understanding of how transcription factors are involved in lymphocyte development still remains a challenge. It has been shown that Egr-2 deficiency results in impaired NKT cell development and defective positive selection of T cells. Here we investigated the development of T, B and NKT cells in Egr-2 transgenic mice and the roles in the regulation of distinct stages of B and T cell development. Methods and Findings The expression of Egr1, 2 and 3 were analysed at different stages of T and B cell development by RT-PCT and results showed that the expression was strictly regulated at different stages. Forced expression of Egr-2 in CD2+ lymphocytes resulted in a severe reduction of CD4+CD8+ (DP) cells in thymus and pro-B cells in bone marrow, which was associated with reduced expression of Notch1 in ISP thymocytes and Pax5 in pro-B cells, suggesting that retraction of Egr-2 at the ISP and pro-B cell stages is important for the activation of lineage differentiation programs. In contrast to reduction of DP and pro-B cells, Egr-2 enhanced the maturation of DP cells into single positive (SP) T and NKT cells in thymus, and immature B cells into mature B cells in bone marrow. Conclusions Our results demonstrate that Egr-2 expressed in restricted stages of lymphocyte development plays a dynamic, but similar role for the development of T, NKT and B cells.

Li, Suling; Symonds, Alistair L. J.; Zhu, Bo; Liu, Mengya; Raymond, Meera V.; Miao, Tizong; Wang, Ping

2011-01-01

142

In vivo expression of interleukin-8, and regulated on activation, normal, T-cell expressed, and secreted, by human germinal centre B lymphocytes  

PubMed Central

T-cell homing within germinal centres (GCs) is required for humoral B-cell responses. However, the mechanisms implicated in the recruitment of T cells into the GC are not completely understood. Here we show, by immunohistology, and Northern and Western blots, that in vivo human GC B lymphocytes can express CxC and CC chemokines. Moreover, B-cell subset-specific experiments reveal that interleukin (IL)-8 and regulated on activation, normal, T-cell expressed, and secreted (RANTES) are predominantly expressed by GC centroblast and centrocytes, suggesting that chemokine expression is essential at stages in which B-lymphocytes engage in active antigen-dependent interactions with T lymphocytes. In keeping with this hypothesis, we show that the T cells recruited into the GC correlatively express the receptors for IL-8 and RANTES. We propose that chemokine expression is a key B-cell function that facilitates T-lymphocyte recruitment into the GCs and supports cognate B-cell : T-cell encounters. Moreover, our data are consistent with the impaired homing of T cells to secondary lymphoid organs in mice that are either deficient in CC and CxC chemokines or their receptors.

Sims-Mourtada, Jennifer C; Guzman-Rojas, Liliana; Rangel, Roberto; Nghiem, Dat X; Ullrich, Stephen E; Guret, Christiane; Cain, Kelly; Martinez-Valdez, Hector

2003-01-01

143

T cells from late tumor-bearing mice express normal levels of p56lck, p59fyn, ZAP-70, and CD3 zeta despite suppressed cytolytic activity  

PubMed Central

Loss of T cell-associated signal transduction molecules has recently been implicated in immune suppression in tumor-bearing hosts. In the present study, we have examined this and related phenomenon extensively in a large number of tumor-bearing mice, analyzed individually. Splenic T cells from tumor-bearing mice were isolated and characterized with respect to the following: (a) levels of three tyrosine kinases, p56lck, p59fyn, and ZAP-70; (b) expression of CD3-zeta; (c) alloreactive responses; and (d) antigen-specific responses. Contrary to recent reports, T cells from tumor-bearing mice were observed to express normal levels of lck, fyn, ZAP-70, and CD3-zeta. Further, T cells showed healthy alloreactive and antigen-specific responses until approximately 3 wk after post tumor challenge, when the tumors constituted approximately 20% of the body weight. Alterations with respect to some parameters were observed only in mice that had been bearing larger tumors for a considerably longer period. As human tumors are unlikely to grow to such large sizes (e.g., > 20% of the total body weight), the significance of the alterations in T cell expression of lck, fyn, ZAP-70, or CD3-zeta in the immune status of cancer patients is unclear. Altogether, these results indicate that alterations in T cell signal transduction molecules do not account for the profound tumor-specific suppression observed during tumor growth.

1995-01-01

144

The Tec kinases Itk and Rlk regulate conventional versus innate T-cell development  

Microsoft Academic Search

Tec family kinases are important components of antigen receptor signaling pathways in B cells, T cells, and mast cells. In T cells, three members of this family, inducible T-cell kinase (Itk), resting lymphocyte kinase (Rlk), and Tec, are expressed. In the absence of Itk and Rlk, T-cell receptor signaling is impaired, with defects in mitogen-activated protein kinase activation, Ca(2+) mobilization,

Amanda L. Prince; Catherine C. Yin; Megan E. Enos; Martin Felices; Leslie J. Berg

2009-01-01

145

Alternative promoter usage at the Notch1 locus supports ligand-independent signaling in T cell development and leukemogenesis  

PubMed Central

Loss of Ikaros has been correlated with Notch activation in T cell acute lymphoblastic leukemia (T-ALL), however, the mechanism remains unknown. We identified promoters in Notch1 that drive expression of Notch1 proteins active in the absence of ligand. Ikaros bound to both canonical and alternative Notch1 promoters and its loss increased permissive chromatin, facilitating recruitment of transcription regulators. At early stages of leukemogenesis, increased basal expression from the canonical and 5’-alternative promoters initiated a feed-back loop, progressively augmenting Notch1 signaling. Ikaros also repressed intragenic promoters that are cryptic in wild-type, poised in pre-leukemic, and active in leukemic cells and which also produced ligand-independent Notch1 proteins. Only ligand-independent Notch1 isoforms were required for Ikaros-mediated leukemogenesis. Notch1 alternative-promoter usage was observed at stages of T cell development dependent on Notch signaling and during T-ALL progression. These studies identify a network of epigenetic and transcriptional regulators that control conventional and unconventional Notch signaling during normal development and leukemogenesis.

Gomez-del Arco, Pablo; Kashiwagi, Mariko; Jackson, Audrey F.; Naito, Taku; Zhang, Jiangwen; Liu, Feifei; Kee, Barbara; Vooijs, Marc; Radtke, Freddy; Redondo, Juan Miguel; Georgopoulos, Katia

2011-01-01

146

Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5  

PubMed Central

The loss of Gimap5 (GTPase of the immune-associated protein 5) gene function is the underlying cause of lymphopenia and autoimmune diabetes in the BioBreeding (BB) rat. The in vivo function of murine gimap5 is largely unknown. We show that selective gene ablation of the mouse gimap5 gene impairs the final intrathymic maturation of CD8 and CD4 T cells and compromises the survival of postthymic CD4 and CD8 cells, replicating findings in the BB rat model. In addition, gimap5 deficiency imposes a block of natural killer (NK)- and NKT-cell differentiation. Development of NK/NKT cells is restored on transfer of gimap5?/? bone marrow into a wild-type environment. Mice lacking gimap5 have a median survival of 15 weeks, exhibit chronic hepatic hematopoiesis, and in later stages show pronounced hepatocyte apoptosis, leading to liver failure. This pathology persists in a Rag2-deficient background in the absence of mature B, T, or NK cells and cannot be adoptively transferred by transplanting gimap5?/? bone marrow into wild-type recipients. We conclude that mouse gimap5 is necessary for the survival of peripheral T cells, NK/NKT-cell development, and the maintenance of normal liver function. These functions involve cell-intrinsic as well as cell-extrinsic mechanisms.

Schulteis, Ryan D.; Chu, Haiyan; Dai, Xuezhi; Chen, Yuhong; Edwards, Brandon; Haribhai, Dipica; Williams, Calvin B.; Malarkannan, Subramaniam; Hessner, Martin J.; Glisic-Milosavljevic, Sanja; Jana, Srikanta; Kerschen, Edward J.; Ghosh, Soumitra; Wang, Demin; Kwitek, Anne E.; Lernmark, Ake; Gorski, Jack

2008-01-01

147

Diacylglycerol Kinases: Regulated Controllers of T Cell Activation, Function, and Development  

PubMed Central

Diacylglycerol kinases (DGKs) are a diverse family of enzymes that catalyze the conversion of diacylglycerol (DAG), a crucial second messenger of receptor-mediated signaling, to phosphatidic acid (PA). Both DAG and PA are bioactive molecules that regulate a wide set of intracellular signaling proteins involved in innate and adaptive immunity. Clear evidence points to a critical role for DGKs in modulating T cell activation, function, and development. More recently, studies have elucidated factors that control DGK function, suggesting an added complexity to how DGKs act during signaling. This review summarizes the available knowledge of the function and regulation of DGK isoforms in signal transduction with a particular focus on T lymphocytes.

Joshi, Rohan P.; Koretzky, Gary A.

2013-01-01

148

Midkine inhibits inducible regulatory T cell differentiation by suppressing the development of tolerogenic dendritic cells.  

PubMed

Midkine (MK), a heparin-binding growth factor, reportedly contributes to inflammatory diseases, including Crohn's disease and rheumatoid arthritis. We previously showed that MK aggravates experimental autoimmune encephalomyelitis (EAE) by decreasing regulatory CD4(+)CD25(+)Foxp3(+) T cells (Tregs), a population that regulates the development of autoimmune responses, although the precise mechanism remains uncertain. In this article, we show that MK produced in inflammatory conditions suppresses the development of tolerogenic dendritic cells (DCregs), which drive the development of inducible Treg. MK suppressed DCreg-mediated expansion of the CD4(+)CD25(+)Foxp3(+) Treg population. DCregs expressed significantly higher levels of CD45RB and produced significantly less IL-12 compared with conventional dendritic cells. However, MK downregulated CD45RB expression and induced IL-12 production by reducing phosphorylated STAT3 levels via src homology region 2 domain-containing phosphatase-2 in DCreg. Inhibiting MK activity with anti-MK RNA aptamers, which bind to the targeted protein to suppress the function of the protein, increased the numbers of CD11c(low)CD45RB(+) dendritic cells and Tregs in the draining lymph nodes and suppressed the severity of EAE, an animal model of multiple sclerosis. Our results also demonstrated that MK was produced by inflammatory cells, in particular, CD4(+) T cells under inflammatory conditions. Taken together, these results suggest that MK aggravates EAE by suppressing DCreg development, thereby impairing the Treg population. Thus, MK is a promising therapeutic target for various autoimmune diseases. PMID:22323540

Sonobe, Yoshifumi; Li, Hua; Jin, Shijie; Kishida, Satoshi; Kadomatsu, Kenji; Takeuchi, Hideyuki; Mizuno, Tetsuya; Suzumura, Akio

2012-03-15

149

Distinct cytokines balance the development of regulatory T cells and interleukin-10-producing regulatory B cells.  

PubMed

Regulatory T cells have been well described and the factors regulating their development and function have been identified. Recently, a growing body of evidence has documented the existence of interleukin-10 (IL-10) -producing B cells, which are called regulatory B10 cells. These cells attenuate autoimmune, inflammatory and transplantation reactions, and the main mechanism of their inhibitory action is the production of IL-10. We show that the production of IL-10 by lipopolysaccharide-stimulated B cells is significantly enhanced by IL-12 and interferon-? and negatively regulated by IL-21 and transforming growth factor-?. In addition, exogenous IL-10 also inhibits B-cell proliferation and the expression of the IL-10 gene in lipopolysaccharide-stimulated B cells. The negative autoregulation of IL-10 production is supported by the observation that the inclusion of anti-IL-10 receptor monoclonal antibody enhances IL-10 production and the proliferation of activated B cells. The effects of cytokines on IL-10 production by B10 cells did not correlate with their effects on B-cell proliferation or on IL-10 production by T cells or macrophages. The cytokine-induced changes in IL-10 production occurred on the level of IL-10 gene expression, as confirmed by increased or decreased IL-10 mRNA expression in the presence of a particular cytokine. The regulatory cytokines modulate the number of IL-10-producing cells rather than augmenting or decreasing the secretion of IL-10 on a single-cell level. Altogether these data show that the production of IL-10 by B cells is under the strict regulatory control of cytokines and that individual cytokines differentially regulate the development and activity of regulatory T cells and IL-10-producing regulatory B cells. PMID:24256319

Holan, Vladimir; Zajicova, Alena; Javorkova, Eliska; Trosan, Peter; Chudickova, Milada; Pavlikova, Michaela; Krulova, Magdalena

2014-04-01

150

Antigen-Specific CD8+ T Cells and the Development of Central Memory during Mycobacterium tuberculosis Infection1  

PubMed Central

Whether true memory T cells develop in the face of chronic infection such as tuberculosis remains controversial. To address this question, we studied CD8+ T cells specific for the Mycobacterium tuberculosis ESAT6-related Ags TB10.3 and TB10.4. The shared epitope TB10.3/10.420–28 is presented by H-2 Kd, and 20–30% of the CD8+ T cells in the lungs of chronically infected mice are specific for this Ag following respiratory infection with M. tuberculosis. These TB10.3/10.420–28-specific CD8+ T cells produce IFN-? and TNF and express CD107 on their cell surface, which indicates their likely role as CTL in vivo. Nearly all of the Ag-specific CD8+ T cells in the lungs of chronically infected mice had a T effector cell phenotype based on their low expression of CD62L and CD45RB. In contrast, a population of TB10.3/10.420–28-specific CD8+ T cells was identified in the lymphoid organs that express high levels of CD62L and CD45RB. Antibiotic treatment to resolve the infection led to a contraction of the Ag-specific CD8+ T cell population and was accompanied by an increase in the proportion of CD8+ T cells with a central memory phenotype. Finally, challenge of memory-immune mice with M. tuberculosis was accompanied by significant expansion of TB10.3/10.420–28-specific CD8+ T cells, which suggests that these cells are in fact functional memory T cells.

Kamath, Arati; Woodworth, Joshua S.M.; Behar, Samuel M.

2011-01-01

151

Suppressor T cells and the regression phase of syngeneic intradermally developing p-815 mastocytomas.  

PubMed

Thymus cells obtained 6, 8 or 10 days after the intradermal injection of P-815 tumor cells into syngeneic DBA/2 mice were, upon adoptive transfer into new hosts, incapable of abrogating the normally observed tumor regression phase. Transfer of cells from day 8 revealed a tendency toward suppression of regression phases; cells from day 6 or 10 were inert or had a rather immunopotentiating effect. Pretreatment of tumor hosts with cyclophosphamide did not result in more pronounced regression phases, nor did this treatment raise the percentage of surviving animals. Injection of cyclophosphamide after tumor cell inoculation resulted in a slight delay of tumor growth, but not in more pronounced regression nor in higher survival rates. Taken together the data suggest that in a weakly immunogenic and highly malignant tumor, suppressor T cells may play a minor role in the subversion of the host's immune response. PMID:6214404

Bertschmann, M; Schären, B; Lüscher, E F

1982-04-01

152

Long-Term Progestin Treatment Inhibits RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted) Gene Expression in Human Endometrial Stromal Cells  

Microsoft Academic Search

RANTES (regulated on activation, normal T cell expressed and secreted) is synthesized by endometrial and endometri- otic stromal cells and circulates in peritoneal fluid. Reports indicate that medroxyprogesterone acetate (MPA) is clini- cally effective in alleviating pelvic pain in the majority of endometriosis patients, which leads us to hypothesize that MPA may be antiinflammatory. Prolonged treatment (8 d) with MPA

DONG ZHAO; DAN I. LEBOVIC; ROBERT N. TAYLOR

153

Cell-Intrinsic Role for NF-kappa B-Inducing Kinase in Peripheral Maintenance but Not Thymic Development of Foxp3+ Regulatory T Cells in Mice  

PubMed Central

NF-?B inducing kinase (NIK, MAP3K14) is a key signaling molecule in non-canonical NF-?B activation, and NIK deficient mice have been instrumental in deciphering the immunologic role of this pathway. Global ablation of NIK prevents lymph node development, impairs thymic stromal development, and drastically reduces B cells. Despite altered thymic selection, T cell numbers are near normal in NIK deficient mice. The exception is CD4+ regulatory T cells (Tregs), which are reduced in the thymus and periphery. Defects in thymic stroma are known to contribute to impaired Treg generation, but whether NIK also plays a cell intrinsic role in Tregs is unknown. Here, we compared intact mice with single and mixed BM chimeric mice to assess the intrinsic role of NIK in Treg generation and maintenance. We found that while NIK expression in stromal cells suffices for normal thymic Treg development, NIK is required cell-intrinsically to maintain peripheral Tregs. In addition, we unexpectedly discovered a cell-intrinsic role for NIK in memory phenotype conventional T cells that is masked in intact mice, but revealed in BM chimeras. These results demonstrate a novel role for NIK in peripheral regulatory and memory phenotype T cell homeostasis.

Murray, Susan E.

2013-01-01

154

Core binding factors are necessary for natural killer cell development and cooperate with Notch signaling during T-cell specification  

PubMed Central

CBF? is the non-DNA binding subunit of the core binding factors (CBFs). Mice with reduced CBF? levels display profound, early defects in T-cell but not B-cell development. Here we show that CBF? is also required at very early stages of natural killer (NK)–cell development. We also demonstrate that T-cell development aborts during specification, as the expression of Gata3 and Tcf7, which encode key regulators of T lineage specification, is substantially reduced, as are functional thymic progenitors. Constitutively active Notch or IL-7 signaling cannot restore T-cell expansion or differentiation of CBF? insufficient cells, nor can overexpression of Runx1 or CBF? overcome a lack of Notch signaling. Therefore, the ability of the prethymic cell to respond appropriately to Notch is dependent on CBF?, and both signals converge to activate the T-cell developmental program.

Guo, Yalin; Maillard, Ivan; Chakraborti, Sankhamala; Rothenberg, Ellen V.

2008-01-01

155

HIV-1 transgenic rat CD4+ T cells develop decreased CD28 responsiveness and suboptimal Lck tyrosine dephosphorylation following activation  

SciTech Connect

Impaired CD4+ T cell responses, resulting in dysregulated T-helper 1 (Th1) effector and memory responses, are a common result of HIV-1 infection. These defects are often preceded by decreased expression and function of the {alpha}/{beta} T cell receptor (TCR)-CD3 complex and of co-stimulatory molecules including CD28, resulting in altered T cell proliferation, cytokine secretion and cell survival. We have previously shown that HIV Tg rats have defective development of T cell effector function and generation of specific effector/memory T cell subsets. Here we identify abnormalities in activated HIV-1 Tg rat CD4+ T cells that include decreased pY505 dephosphorylation of Lck (required for Lck activation), decreased CD28 function, reduced expression of the anti-apoptotic molecule Bcl-xL, decreased secretion of the mitogenic lympokine interleukin-2 (IL-2) and increased activation induced apoptosis. These events likely lead to defects in antigen-specific signaling and may help explain the disruption of Th1 responses and the generation of specific effector/memory subsets in transgenic CD4+ T cells.

Yadav, Anjana [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States); Pati, Shibani [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States); Nyugen, Anhthu [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States); Barabitskaja, Oxana [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States); Mondal, Prosanta [Department of Epidemiology and Prevention, Institute of Human Virology, University of Maryland, Baltimore, MD 21201 (United States); Anderson, Michael [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States); Gallo, Robert C. [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States); Huso, David L. [Division of Comparative Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Reid, William [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States)]. E-mail: reid@umbi.umd.edu

2006-09-30

156

Nonclassical MHC class I-dependent invariant T cells are evolutionarily conserved and prominent from early development in amphibians  

PubMed Central

Human and murine MHC nonclassical class Ib-restricted invariant T (iT) cell subsets, such as invariant natural killer T cells (iNKT) and mucosal-associated invariant T cells, have specialized functions early in immune responses, especially in modulating subsequent adaptive immune responses. Here, we characterize a prominent iT population in the amphibian Xenopus laevis and show the requirement of the class Ib molecule, Xenopus nonclassical gene 10, in its differentiation and function. Using Xenopus nonclassical gene 10 tetramers and RNAi loss of function by transgenesis, we identified a large class Ib-dependent CD8?/CD4? iT subset in unmanipulated frogs and tadpoles. This population is critical for antiviral immunity during early larval stages when classical MHC class Ia function is suboptimal. Furthermore, in young tadpoles with low class Ia expression, deep sequencing revealed additional preponderant invariant T cell receptor (TCR)? rearrangements, implying other iT cell subsets and a predominant selection process mediated by other class Ib molecules. The restriction and requirement of class Ib molecules for development and antiviral immunity of a mammalian iNKT or mucosal-associated invariant T cell counterpart in the amphibian Xenopus show the importance of iT cells in the emergence and evolution of the adaptive immune system.

Edholm, Eva-Stina; Albertorio Saez, Liz-Marie; Gill, Ann L.; Gill, Steven R.; Grayfer, Leon; Haynes, Nikesha; Myers, Jason R.; Robert, Jacques

2013-01-01

157

Nonclassical MHC class I-dependent invariant T cells are evolutionarily conserved and prominent from early development in amphibians.  

PubMed

Human and murine MHC nonclassical class Ib-restricted invariant T (iT) cell subsets, such as invariant natural killer T cells (iNKT) and mucosal-associated invariant T cells, have specialized functions early in immune responses, especially in modulating subsequent adaptive immune responses. Here, we characterize a prominent iT population in the amphibian Xenopus laevis and show the requirement of the class Ib molecule, Xenopus nonclassical gene 10, in its differentiation and function. Using Xenopus nonclassical gene 10 tetramers and RNAi loss of function by transgenesis, we identified a large class Ib-dependent CD8(-)/CD4(-) iT subset in unmanipulated frogs and tadpoles. This population is critical for antiviral immunity during early larval stages when classical MHC class Ia function is suboptimal. Furthermore, in young tadpoles with low class Ia expression, deep sequencing revealed additional preponderant invariant T cell receptor (TCR)? rearrangements, implying other iT cell subsets and a predominant selection process mediated by other class Ib molecules. The restriction and requirement of class Ib molecules for development and antiviral immunity of a mammalian iNKT or mucosal-associated invariant T cell counterpart in the amphibian Xenopus show the importance of iT cells in the emergence and evolution of the adaptive immune system. PMID:23940320

Edholm, Eva-Stina; Albertorio Saez, Liz-Marie; Gill, Ann L; Gill, Steven R; Grayfer, Leon; Haynes, Nikesha; Myers, Jason R; Robert, Jacques

2013-08-27

158

SDF-1? degrades, while gp120 upregulates BimEL: implications for the development of T cell memory  

PubMed Central

Following a primary immune response, T cell memory occurs when a subset of antigen specific T cells resist peripheral selection by acquiring resistance to TCR induced death. Recent data have implicated Bim as an essential mediator of the contraction phase of T cell immunity. Herein, we describe that SDF-1? ligation of CXCR4 on activated T cells, promotes two parallel processes which favor survival, phospho-inactivation of Foxo3A as well as BimEL degradation, both in an Akt and Erk dependent manner. Activated primary CD4 T cells treated with SDF-1? therefore become resistant to the pro-apoptotic effects of TCR ligation or IL-2 deprivation and accumulate cells of a memory phenotype. Unlike SDF-1?, gp120 ligation of CXCR4 has the opposite effect as it causes p38 dependent BimEL upregulation. However when activated CD4 T cells are treated with both gp120 and SDF-1?, the SDF-1? driven effects of BimEL degradation and acquired resistance to TCR induced death predominate. These results provide a novel causal link between SDF-1? induced chemotaxis, degradation of BimEL and the development of CD4 T cell memory.

Trushin, Sergey A.; Carena, Alberto A.; Bren, Gary D.; Rizza, Stacey A.; Dong, Xiangyang; Abraham, Roshini S.; Badley, Andrew D.

2012-01-01

159

CD4+ T cell expression of MyD88 is essential for normal resolution of Chlamydia muridarum genital tract infection.  

PubMed

Resolution of Chlamydia genital tract infection is delayed in the absence of MyD88. In these studies, we first used bone marrow chimeras to demonstrate a requirement for MyD88 expression by hematopoietic cells in the presence of a wild-type epithelium. Using mixed bone marrow chimeras we then determined that MyD88 expression was specifically required in the adaptive immune compartment. Furthermore, adoptive transfer experiments revealed that CD4(+) T cell expression of MyD88 was necessary for normal resolution of genital tract infection. This requirement was associated with a reduced ability of MyD88(-/-)CD4(+) T cells to accumulate in the draining lymph nodes and genital tract when exposed to the same inflammatory milieu as wild-type CD4(+) T cells. We also demonstrated that the impaired infection control we observed in the absence of MyD88 could not be recapitulated by deficiencies in TLR or IL-1R signaling. In vitro, we detected an increased frequency of apoptotic MyD88(-/-)CD4(+) T cells upon activation in the absence of exogenous ligands for receptors upstream of MyD88. These data reveal an intrinsic requirement for MyD88 in CD4(+) T cells during Chlamydia infection and indicate that the importance of MyD88 extends beyond innate immune responses by directly influencing adaptive immunity. PMID:24038087

Frazer, Lauren C; Sullivan, Jeanne E; Zurenski, Matthew A; Mintus, Margaret; Tomasak, Tammy E; Prantner, Daniel; Nagarajan, Uma M; Darville, Toni

2013-10-15

160

Generation of Dhx9 deficient clones in T cell development with a mitotic recombination technique  

PubMed Central

Mitotic recombination is an effective tool for generating mutant clones in somatic tissues. Due to difficulties associated with detecting and quantifying mutant clones in mice, this technique is limited to analysis of growth related phenotypes induced by loss function of tumor suppressor genes. Here, we used the polymorphic CD45.1/CD45.2 alleles on chromosome 1 as pan-hematopoietic markers to track mosaic clones generated through mitotic recombination in developing T cells. We show that lineage specific mitotic recombination can be induced and reliably detected as CD45.1 or CD45.2 homozygous clones from the CD45.1/CD45.2 heterozygous background. We have applied this system in the analysis of a lethal mutation in the Dhx9 gene. Mosaic analysis revealed a stage specific role for Dhx9 during T cell maturation. Thus, the experimental system described in this study offers a practical means for mosaic analysis of germline mutations in the hematopoietic system.

Zhu, Yi; Liu, Shiwei; Yin, Qili; Xu, Tian; Wu, Xiaohui; Zhuang, Yuan

2012-01-01

161

Aire-dependent thymic development of tumor-associated regulatory T cells*  

PubMed Central

Despite considerable interest in the modulation of tumor-associated Foxp3+ regulatory T cells (Tregs) for therapeutic benefit, little is known about the developmental origins of these cells and the nature of the antigens that they recognize. Here, we identified an endogenous population of antigen-specific Tregs (termed “MJ23” Tregs) found recurrently enriched in the tumors of mice with oncogene-driven prostate cancer. MJ23 Tregs were not reactive to a tumor-specific antigen, but instead recognized a prostate-associated antigen that was present in tumor-free mice. MJ23 Tregs underwent Aire-dependent thymic development in both male and female mice. Thus Aire-mediated expression of peripheral tissue antigens drives the thymic development of a subset of organ-specific Tregs, which are likely co-opted by tumors developing within the associated organ.

Malchow, Sven; Leventhal, Daniel S.; Nishi, Saki; Fischer, Benjamin I.; Shen, Lynn; Paner, Gladell P.; Amit, Ayelet S.; Kang, Chulho; Geddes, Jenna E.; Allison, James P.; Socci, Nicholas D.; Savage, Peter A.

2013-01-01

162

Cell-Intrinsic NF-?B Activation Is Critical for the Development of Natural Regulatory T Cells in Mice  

Microsoft Academic Search

BackgroundNaturally occurring CD4+CD25+Foxp3+ regulatory T (Treg) cells develop in the thymus and represent a mature T cell subpopulation critically involved in maintaining peripheral tolerance. The differentiation of Treg cells in the thymus requires T cell receptor (TCR)\\/CD28 stimulation along with cytokine-promoted Foxp3 induction. TCR-mediated nuclear factor kappa B (NF-?B) activation seems to be involved in differentiation of Treg cells because

Eva Gückel; Silke Frey; Mario M. Zaiss; Georg Schett; Sankar Ghosh; Reinhard E. Voll

2011-01-01

163

The BTB–zinc finger transcriptional regulator PLZF controls the development of invariant natural killer T cell effector functions  

Microsoft Academic Search

Invariant natural killer T cells (iNKT cells) have an innate immunity–like rapidity of response and the ability to modulate the effector functions of other cells. We show here that iNKT cells specifically expressed the BTB–zinc finger transcriptional regulator PLZF. In the absence of PLZF, iNKT cells developed, but they lacked many features of innate T cells. PLZF-deficient iNKT cells accumulated

Damian Kovalovsky; Olisambu U Uche; Sonia Eladad; Robin M Hobbs; Woelsung Yi; Eric Alonzo; Kevin Chua; Maggie Eidson; Hye-Jung Kim; Jin S Im; Pier Paolo Pandolfi; Derek B Sant'Angelo

2008-01-01

164

Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells  

Microsoft Academic Search

Naturally occurring CD251CD41 regulatory T cells are engaged in the maintenance of immunological self-tolerance and down-regulation of various immune responses. Recent studies with mice showed that Foxp3, which encodes the transcription factor Scurfin, is a master regulatory gene for the development and function of CD251CD41 regulatory T cells. Here we examined the role of FOXP3 in human CD251CD41 regulatory T

Haruhiko Yagi; Takashi Nomura; Kyoko Nakamura; Sayuri Yamazaki; Toshio Kitawaki; Shohei Hori; Michiyuki Maeda; Masafumi Onodera; Takashi Uchiyama; Shingo Fujii; Shimon Sakaguchi

2004-01-01

165

Zebrafish Mutants with Disrupted Early T cell and Thymus Development Identified in Early Pressure Screen1  

PubMed Central

Generation of mature T lymphocytes requires an intact hematopoietic stem cell compartment and functional thymic epithelium. We used the zebrafish (Danio rerio) to isolate mutations that affect the earliest steps in T lymphopoiesis and thymic organogenesis. Here we describe the results of a genetic screen in which gynogenetic diploid offspring from heterozygous females were analyzed by whole mount in situ hybridization for the expression of rag-1. In order to assess immediately if a global defect in hematopoiesis resulted in the mutant phenotype, ?-embryonic globin expression was simultaneously assayed for multilineage defects. In this report we present the results obtained with this strategy and show representative mutant phenotypes affecting early steps in T cell development and/or thymic epithelial cell development. We discuss the advantage of this strategy and the general usefulness of the zebrafish as a model system for vertebrate lymphopoiesis and thymic organogenesis.

Trede, Nikolaus S.; Ota, Tatsuya; Kawasaki, Hirohide; Paw, Barry H.; Katz, Tammisty; Demarest, Bradley; Hutchinson, Sarah; Zhou, Yi; Hersey, Candace; Zapata, Agustin; Amemiya, Chris T; Zon, Leonard I.

2008-01-01

166

Development of CD4+ macrophages from intrathymic T cell progenitors is induced by thymic epithelial cells.  

PubMed

It was recently demonstrated that there are CD4(+) macrophages, which exhibit strong phagocytic activity, in the thymus. They are suggested to play an important role for the elimination of apoptotic thymocytes. However, the origin and nature of CD4(+) macrophages in the thymus remain unexplored. In this study, we describe that the most immature intrathymic progenitors (CD25(-)/CD44(+)/FcR(+)) give rise to CD4(+) macrophages by oncostatin M-responsive thymic epithelial cells (ORTEC) in an IL-7-dependent manner. Neither conditioned medium of ORTEC nor a mixture of cytokines induced CD4(+) macrophages, and oncostatin M receptor was not expressed in thymocytes, suggesting that the development of CD4(+) macrophages from the immature thymocytes requires a direct interaction with ORTEC. These results collectively suggest that the development of CD4(+) macrophages from the intrathymic T cell progenitors is induced by thymic epithelial cells. PMID:15383565

Esashi, Eiji; Ito, Hiroaki; Ishihara, Katsuhiko; Hirano, Toshio; Koyasu, Shigeo; Miyajima, Atsushi

2004-10-01

167

Incomplete Normalization of Regulatory T-Cell Frequency in the Gut Mucosa of Colombian HIV-Infected Patients Receiving Long-Term Antiretroviral Treatment  

PubMed Central

Introduction To evaluate the effect of late initiation of HAART and poor immune reconstitution on the frequency of regulatory T-cells (Treg) in the peripheral blood and gut of HIV-infected patients, we studied Colombian HIV-infected patients who had been on suppressive HAART for at least one year. They had undetectable viremia but were either immunological responders (HIR); (CD4 counts >500 cells/µl) or non-immunological responders (NIR); (CD4 T-cell count <300 cells/µl). Untreated HIV-infected patients and uninfected controls from the same region were also evaluated. Methods Frequency and phenotype of regulatory T-cells (Treg) were analyzed in gut biopsies and blood samples. The functional effect of Treg depletion on CMV and HIV responses was determined. Markers of immune activation and circulating LPS levels were quantified. Results Untreated patients exhibited high Treg frequency in PBMC and gut, and their Treg express high levels of CTLA-4 and PD-1. Although HAART significantly decreased mucosal Treg frequency, it did not normalize it in any of the treated groups (HIR and NIR patients). Treg normalization was observed in the blood of HIR patients following HAART, but did not occur in NIR patients. Treg from HIV-infected patients (treated or not) suppressed HIV and hCMV-specific T-cells from gut and blood. Plasma LPS levels and percentage of HLA-DR+CD38+ T-cells were significantly elevated in all infected groups compared to controls. Conclusions These findings suggest that control of viral replication is not sufficient to normalize gut Treg frequency in patients, independent of their response to HAART. Furthermore, persistence of functional Treg in the gut appears to be associated with the failure of HAART to repair mucosal damage.

Rueda, Cesar M.; Velilla, Paula A.

2013-01-01

168

TRIM28 mediates chromatin modifications at the TCR? enhancer and regulates the development of T and natural killer T cells  

PubMed Central

T-cell receptor–? (TCR?) rearrangement in CD4+CD8+ double-positive immature thymocytes is a prerequisite for production of ?? T cells and invariant natural killer T cells. This developmental event is regulated by the TCR? enhancer (E?), which induces chromatin modification and recruitment of the recombination-activating proteins Rag1 and Rag2. However, the molecular mechanism underlying the activation and long-range action of E? remains incompletely understood. We show here that the chromatin-modifying factor TRIM28 is highly expressed in double-positive thymocytes and persistently phosphorylated at serine 473. TRIM28 binds to E? and induces histone 3 lysine 4 trimethylation in the E? and distant regions of the TCR? locus, coupled with recruitment of Rag proteins. T-cell–conditional ablation of TRIM28 impaired TCR? gene rearrangement and compromised the development of ?? T cells and invariant natural killer T cells. These findings establish TRIM28 as a unique regulator of thymocyte development and highlight an epigenetic mechanism involving TRIM28-mediated active chromatin modification in the TCR? locus.

Zhou, Xiao-Fei; Yu, Jiayi; Chang, Mikyoung; Zhang, Minying; Zhou, Dapeng; Cammas, Florence; Sun, Shao-Cong

2012-01-01

169

Quantitative and temporal requirements revealed for Zap70 catalytic activity during T cell development.  

PubMed

The catalytic activity of Zap70 is crucial for T cell antigen receptor (TCR) signaling, but the quantitative and temporal requirements for its function in thymocyte development are not known. Using a chemical-genetic system to selectively and reversibly inhibit Zap70 catalytic activity in a model of synchronized thymic selection, we showed that CD4(+)CD8(+) thymocytes integrate multiple, transient, Zap70-dependent signals over more than 36 h to reach a cumulative threshold for positive selection, whereas 1 h of signaling was sufficient for negative selection. Titration of Zap70 activity resulted in graded reductions in positive and negative selection but did not decrease the cumulative TCR signals integrated by positively selected OT-I cells, which revealed heterogeneity, even among CD4(+)CD8(+) thymocytes expressing identical TCRs undergoing positive selection. PMID:24908390

Au-Yeung, Byron B; Melichar, Heather J; Ross, Jenny O; Cheng, Debra A; Zikherman, Julie; Shokat, Kevan M; Robey, Ellen A; Weiss, Arthur

2014-07-01

170

Thymus-Derived Glucocorticoids and the Regulation of Antigen-Specific T-Cell Development  

Microsoft Academic Search

Bidirectional interactions of both a stimulatory and inhibitory nature occur between the neuroendocrine and the immune systems, and these interactions play an important modulatory role during T-cell ontogeny. Specifically, glucocorticoids potently induce apoptosis in thymocytes and activated T cells, but can also rescue these cells from activation-induced cell death. The objective of this review is to discuss current data on

Eva Tolosa; Jonathan D. Ashwell

1999-01-01

171

Repetitive Pertussis Toxin Promotes Development of Regulatory T Cells and Prevents Central Nervous System Autoimmune Disease  

PubMed Central

Bacterial and viral infections have long been implicated in pathogenesis and progression of multiple sclerosis (MS). Incidence and severity of its animal model experimental autoimmune encephalomyelitis (EAE) can be enhanced by concomitant administration of pertussis toxin (PTx), the major virulence factor of Bordetella pertussis. Its adjuvant effect at the time of immunization with myelin antigen is attributed to an unspecific activation and facilitated migration of immune cells across the blood brain barrier into the central nervous system (CNS). In order to evaluate whether recurring exposure to bacterial antigen may have a differential effect on development of CNS autoimmunity, we repetitively administered PTx prior to immunization. Mice weekly injected with PTx were largely protected from subsequent EAE induction which was reflected by a decreased proliferation and pro-inflammatory differentiation of myelin-reactive T cells. Splenocytes isolated from EAE-resistant mice predominantly produced IL-10 upon re-stimulation with PTx, while non-specific immune responses were unchanged. Longitudinal analyses revealed that repetitive exposure of mice to PTx gradually elevated serum levels for TGF-? and IL-10 which was associated with an expansion of peripheral CD4+CD25+FoxP3+ regulatory T cells (Treg). Increased frequency of Treg persisted upon immunization and thereafter. Collectively, these data suggest a scenario in which repetitive PTx treatment protects mice from development of CNS autoimmune disease through upregulation of regulatory cytokines and expansion of CD4+CD25+FoxP3+ Treg. Besides its therapeutic implication, this finding suggests that encounter of the immune system with microbial products may not only be part of CNS autoimmune disease pathogenesis but also of its regulation.

Weber, Martin S.; Benkhoucha, Mahdia; Lehmann-Horn, Klaus; Hertzenberg, Deetje; Sellner, Johann; Santiago-Raber, Marie-Laure; Chofflon, Michel; Hemmer, Bernhard

2010-01-01

172

Expression and regulation of lincRNAs during T cell development and differentiation  

PubMed Central

Although lincRNAs are implicated in gene regulation in various tissues, little is known about lincRNA transcriptomes in the T cell lineages. Here we identify 1,524 lincRNA clusters in 42 T cell samples from early T cell progenitors to terminally differentiated T helper (TH) subsets. Our analysis revealed highly dynamic and cell-specific expression patterns of lincRNAs during T cell differentiation. Importantly, these lincRNAs are located in genomic regions enriched for protein-coding genes with immune-regulatory functions. Many of them are bound and regulated by the key T cell transcription factors T-bet, GATA-3, STAT4 and STAT6. We demonstrate that the lincRNA LincR-Ccr2-5?AS, together with GATA-3, is an essential component of a regulatory circuit in TH2-specific gene expression and important for TH2 cell migration.

Hu, Gangqing; Tang, Qingsong; Sharma, Suveena; Yu, Fang; Escobar, Thelma M.; Muljo, Stefan A.; Zhu, Jinfang; Zhao, Keji

2013-01-01

173

Normalization of the Lymph Node T Cell Stromal Microenvironment in lpr/lpr Mice Is Associated with SU5416-Induced Reduction in Autoantibodies  

PubMed Central

The vascular-stromal elements of lymph nodes can play important roles in regulating the activities of the lymphocytes within. During model immune responses, the vascular-stromal compartment has been shown to undergo proliferative expansion and functional alterations. The state of the vascular-stromal compartment and the potential importance of this compartment in a spontaneous, chronic model of autoimmunity have not been well studied. Here, we characterize the vascular expansion in MRL-lpr/lpr lymph nodes and attempt to ask whether inhibiting this expansion can interfere with autoantibody generation. We show that characteristics of vascular expansion in enlarging MRL-lpr/lpr lymph nodes resemble that of the VEGF-dependent expansion that occurs in wild-type mice after model immunization. Surprisingly, treatment with SU5416, an inhibitor of VEGF and other receptor tyrosine kinases, did not have sustained effects in inhibiting vascular growth, but attenuated the anti-dsDNA response and altered the phenotype of the double negative T cells that are expanded in these mice. In examining for anatomic correlates of these immunologic changes, we found that the double negative T cells are localized within ectopic follicles around a central B cell patch and that these T cell-rich areas lack the T zone stromal protein ER-TR7 as well as other elements of a normal T zone microenvironment. SU5416 treatment disrupted these follicles and normalized the association between T zone microenvironmental elements and T cell-rich areas. Recent studies have shown a regulatory role for T zone stromal elements. Thus, our findings of the association of anti-dsDNA responses, double negative T cell phenotype, and altered lymphocyte microenvironment suggest the possibility that lymphocyte localization in ectopic follicles protects them from regulation by T zone stromal elements and functions to maintain autoimmune responses. Potentially, altering the lymphocyte microenvironment that is set up by the vascular-stromal compartment can be a means by which to control undesired autoimmune responses.

Chyou, Susan; Tian, Sha; Ekland, Eric H.; Lu, Theresa T.

2012-01-01

174

The major CD8 T cell effector memory subset in the normal and Chlamydia trachomatis-infected human endocervix is low in perforin  

PubMed Central

Background The local tissue microenvironment plays an important role in the induction, homing, maintenance and development of effector functions of T cells. Thus, site-specific differences in phenotypes of mucosal and systemic T cell populations have been observed. Chlamydia trachomatis most commonly infects the endocervix in women, yet little is known about Chlamydia-specific effector T cell immunity at this unique mucosal site. Our previous flow-cytometry-based study of cervical-cytobrush retrieved cells indicated that CD8 T cells are significantly increased in the C. trachomatis-infected human endocervix. The cytolytic function of CD8 T cells is important in the protective immunity against many intracellular pathogens, and requires the cytolytic granule perforin to facilitate the entry of other molecules that mediate the lysis of target cells. Determination of perforin expression of the CD8 T cell population in the endocervix would therefore provide insights on the granule-mediated cytolytic potential of these cells at this site. Results Our histological data revealed that C. trachomatis-infected tissues have significantly higher numbers of CD3 and CD8 T cells compared to non-infected tissues (p<0.01), and that the majority of CD8+ cells do not express perforin in situ. A subsequent flow cytometric analysis of paired blood and endocervix-derived cells (n=16) revealed that while all the CD8 T cell subsets: naïve, effector memory (TEM), central memory (TCM) and terminally differentiated effector memory (TEMRA) can be found in the blood, the endocervix is populated mainly by the TEM CD8 T cell subset. Our data also showed that perforin expression in the TEM population is significantly lower in the endocervix than in the blood of C. trachomatis positive women (n=15; p<0.0001), as well as in C. trachomatis-negative individuals (n=6; p<0.05). Interestingly, our in vitro co-culture study suggests that the exposure of HeLa 229 cervical epithelial cells to IFN gamma could potentially induce a decrease in perforin content in CD8 TEM cells in the same microenvironment. Conclusions The low perforin content of CD8 TEM cells in the endocervix, the local site of C. trachomatis infection in women, may reflect the unique immunological environment that balances immune protection against sexually transmitted infections and immune- tolerance to support conception.

2012-01-01

175

T cells fail to develop in the human skin-cell explants system; an inconvenient truth  

Microsoft Academic Search

Background  Haplo-identical hematopoietic stem cell (HSC) transplantation is very successful in eradicating haematological tumours, but\\u000a the long post-transplant T-lymphopenic phase is responsible for high morbidity and mortality rates. Clark et al. have described a skin-explant system capable of producing host-tolerant donor-HSC derived T-cells. Because this T-cell production\\u000a platform has the potential to replenish the T-cell levels following transplantation, we set out

Bob Meek; Catharina HMJ Van Elssen; Mirelle JAJ Huijskens; Sjoukje JC van der Stegen; Siebe Tonnaer; Stijn BJ Lumeij; Joris Vanderlocht; Mark A Kirkland; Reinout Hesselink; Wilfred TV Germeraad; Gerard MJ Bos

2011-01-01

176

Dendritic cell-MHC class II and Itk regulate functional development of regulatory innate memory CD4+ T cells in bone marrow transplantation.  

PubMed

MHC class II (MHCII)-influenced CD4(+) T cell differentiation and function play critical roles in regulating the development of autoimmunity. The lack of hematopoietic MHCII causes autoimmune disease that leads to severe wasting in syngeneic recipients. Using murine models of bone marrow transplantation (BMT), we find that MHCII(-/-)?wild-type BMT developed disease, with defective development of innate memory phenotype (IMP, CD44(hi)/CD62L(lo)) CD4(+) T cells. Whereas conventional regulatory T cells are unable to suppress pathogenesis, IMP CD4(+) T cells, which include conventional regulatory T cells, can suppress pathogenesis in MHCII(-/-)?wild-type chimeras. The functional development of IMP CD4(+) T cells requires hematopoietic but not thymic MHCII. B cells and hematopoietic CD80/86 regulate the population size, whereas MHCII expression by dendritic cells is sufficient for IMP CD4(+) T cell functional development and prevention of pathogenesis. Furthermore, the absence of Tec kinase IL-2-inducible T cell kinase in MHCII(-/-) donors leads to preferential development of IMP CD4(+) T cells and partially prevents pathogenesis. We conclude that dendritic cells-MHCII and IL-2-inducible T cell kinase regulate the functional development of IMP CD4(+) T cells, which suppresses the development of autoimmune disorder in syngeneic BMTs. PMID:24610010

Huang, Weishan; Qi, Qian; Hu, Jianfang; Huang, Fei; Laufer, Terri M; August, Avery

2014-04-01

177

Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting  

Microsoft Academic Search

INTERLEUKIN-2 (IL-2) is a lymphocytotropic hormone which is thought to have a key role in the immune response of mammalian cells. It is produced by a subpopulation of activated T-lymphocytes and acts in vitro as the principal auto- and paracrine T-cell growth factor (for reviews see refs 1-3). IL-2 is, however, not the sole T-cell growth factor4,5, nor does it

Hubert Schorle; Thomas Holtschke; Thomas Hünig; Anneliese Schimpl; Ivan Horak

1991-01-01

178

The role of Tec family kinases in T cell development and function  

Microsoft Academic Search

Three members of the Tec family kinases, Itk, Rlk and Tec, have been implicated in signaling downstream of the T cell receptor (TCR). The activity of these kinases in T cells has been shown to be important for the full activation of phospholipase C-gamma1 (PLC-gamma1). Disruption of Tec family signaling in Itk-\\/- and Rlk-\\/-Itk-\\/- mice has multiple effects on T

Julie Ann Lucas; Andrew Todd Miller; Luana O. Atherly; Leslie J. Berg

2003-01-01

179

Targeted Sos1 deletion reveals its critical role in early T-cell development  

PubMed Central

Activation of the small G protein Ras is required for thymocyte differentiation. In thymocytes, Ras is activated by the Ras guanine exchange factors (RasGEFs) Sos1, Sos2, and RasGRP1. We report the development of a floxed allele of sos1 to assess the role of Sos1 during thymocyte development. Sos1 was required for pre–T-cell receptor (pre-TCR)– but not TCR-stimulated developmental signals. Sos1 deletion led to a partial block at the DN-to-DP transition. Sos1-deficient thymocytes showed reduced pre-TCR–stimulated proliferation, differentiation, and ERK phosphorylation. In contrast, TCR-stimulated positive selection, and negative selection under strong stimulatory conditions, remained intact in Sos1-deficient mice. Comparison of RasGEF expression at different developmental stages showed that relative to Sos2 and RasGRP1, Sos1 is most abundant in DN thymocytes, but least abundant in DP thymocytes. These data reveal that Sos1 is uniquely positioned to affect signal transduction early in thymocyte development.

Kortum, Robert L.; Sommers, Connie L.; Alexander, Clayton P.; Pinski, John M.; Li, Wenmei; Grinberg, Alex; Lee, Jan; Love, Paul E.; Samelson, Lawrence E.

2011-01-01

180

CD4 T cells with effector memory phenotype and function develop in the sterile environment of the fetus.  

PubMed

The T cell compartment is considered to be naïve and dedicated to the development of tolerance during fetal development. We have identified and characterized a population of fetally developed CD4 T cells with an effector memory phenotype (TEM), which are present in cord blood. This population is polyclonal and has phenotypic features similar to those of conventional adult memory T cells, such as CD45RO expression. These cells express low levels of CD25 but are distinct from regulatory T cells because they lack Foxp3 expression. After T cell receptor activation, neonatal TEM cells readily produced tumor necrosis factor-? (TNF-?) and granulocyte-macrophage colony-stimulating factor (GM-CSF). We also detected interferon-? (IFN-?)-producing T helper 1 (TH1) cells and interleukin-4 (IL-4)/IL-13-producing TH2-like cells, but not IL-17-producing cells. We used chemokine receptor expression patterns to divide this TEM population into different subsets and identified distinct transcriptional programs using whole-genome microarray analysis. IFN-? was found in CXCR3(+) TEM cells, whereas IL-4 was found in both CXCR3(+) TEM cells and CCR4(+) TEM cells. CCR6(+) TEM cells displayed a genetic signature that corresponded to TH17 cells but failed to produce IL-17A. However, the TH17 function of TEM cells was observed in the presence of IL-1? and IL-23. In summary, in the absence of reported pathology or any major infectious history, T cells with a memory-like phenotype develop in an environment thought to be sterile during fetal development and display a large variety of inflammatory effector functions associated with CD4 TH cells at birth. PMID:24871133

Zhang, Xiaoming; Mozeleski, Brian; Lemoine, Sebastien; Dériaud, Edith; Lim, Annick; Zhivaki, Dania; Azria, Elie; Le Ray, Camille; Roguet, Gwenaelle; Launay, Odile; Vanet, Anne; Leclerc, Claude; Lo-Man, Richard

2014-05-28

181

Thymic regulatory T cells  

Microsoft Academic Search

Several types of T regulatory (Treg) cells have been described in both mice and humans, including natural or professional (CD4+CD25+ T cells) and adaptive (Th3 and Tr1 cells) Treg cells. The former develops in the thymus and results in an endogeneous long-lived population of self-antigen-specific T cells in the periphery poised to prevent potentially autoimmune reactions. The second subset develops

Enrico Maggi; Lorenzo Cosmi; Francesco Liotta; Paola Romagnani; Sergio Romagnani; Francesco Annunziato

2005-01-01

182

Thymus-independent development and negative selection of T cells expressing T cell receptor alpha/beta in the intestinal epithelium: evidence for distinct circulation patterns of gut- and thymus-derived T lymphocytes  

PubMed Central

We demonstrate that mouse intestinal intraepithelial lymphocytes (IEL) can be divided into subsets based on the differential expression of functional T cell receptor alpha/beta (TCR-alpha/beta) signaling complexes. Two subsets, CD4+ 8 alpha + beta - and CD8 alpha + beta -, are refractory to stimulation with anti-TCR-alpha/beta and contain high frequencies of potentially self-reactive cells. In contrast, the CD4+ and CD8 alpha + beta + IEL subsets are responsive to anti-TCR- alpha/beta and depleted of potentially self-reactive cells. The analysis of fetal liver radiation chimeras using adult thymectomized recipients demonstrates that the four TCR-alpha/beta + IEL subsets are generated in normal numbers in the absence of the thymus. Moreover, expression of the major histocompatibility complex class II-encoded I-E molecule and Mls1a in the gut of the athymic host results in the negative selection of potentially self-reactive T cells expressing V beta 11 and V beta 6, respectively, from those IEL subsets that express functional TCR-alpha/beta signaling complexes. Neither the spleen nor the Peyer's patches of athymic recipients contain T cells of donor origin. In contrast, normal numbers of phenotypically and functionally mature CD4+ and CD8 alpha + beta + T cells of donor origin are found in the lamina propria of chimeric animals. The phenotypic analysis of lymphocytes obtained from Ly5 congenic parabionts reveals that peripheral T cells migrate rapidly to the Peyer's patches and lamina propria, but not to the intestinal epithelium. Taken together, these results demonstrate that the intestinal epithelium is a thymus- independent site of T lymphopoiesis, where selection of the T cell repertoire involves the deletion of potentially self-reactive cells in situ. Moreover, the appearance of donor-derived, phenotypically mature T cells, exclusively in the lamina propria of athymic radiation chimeras, suggests that mature IEL expressing functional TCR-alpha/beta migrate to this site.

1992-01-01

183

Lineage divergence at the first TCR dependent checkpoint: preferential ?? and impaired ?? T cell development in non-obese diabetic (NOD) mice1  

PubMed Central

The first TCR-dependent checkpoint in the thymus determines ?? vs. ?? T lineage fate and sets the stage for later T cell differentiation decisions. We had previously shown that early T cells in NOD mice that are unable to rearrange a TCR exhibit a defect in checkpoint enforcement at this stage. To determine if T cell progenitors from wild type NOD mice also exhibit cell-autonomous defects in development we investigated their differentiation in the Notch-ligand presenting OP9-DL1 co-culture system, as well as by analysis of T cell development in vivo. Cultured CD4 and CD8 double negative (DN) cells from NOD mice exhibited major defects in the generation of CD4 and CD8 double positive (DP) ??T cells, while ??T cell development from bipotent precursors was enhanced. Limiting dilution and single cell experiments show that the divergent effects on ?? and ?? T cell development did not spring from biased lineage choice but from increased proliferation of ??T cells and impaired accumulation of ??T lineage DP cells. In vivo, NOD early T cell subsets in the thymus also show characteristics indicative of defective ?-selection, and peripheral ??T cells are poorly established in mixed bone marrow chimeras, contrasting with strong ??T as well as B cell repopulation. Thus, NOD T cell precursors reveal divergent, lineage-specific differentiation abnormalities in vitro and in vivo from the first TCR-dependent developmental choice point, which may have consequences for subsequent lineage decisions and effector functions.

Feng, Ni; Vegh, Patricia; Rothenberg, Ellen V.; Yui, Mary A.

2014-01-01

184

From Murine to Human Nude/SCID: The Thymus, T-Cell Development and the Missing Link  

PubMed Central

Primary immunodeficiencies (PIDs) are disorders of the immune system, which lead to increased susceptibility to infections. T-cell defects, which may affect T-cell development/function, are approximately 11% of reported PIDs. The pathogenic mechanisms are related to molecular alterations not only of genes selectively expressed in hematopoietic cells but also of the stromal component of the thymus that represents the primary lymphoid organ for T-cell differentiation. With this regard, the prototype of athymic disorders due to abnormal stroma is the Nude/SCID syndrome, first described in mice in 1966. In man, the DiGeorge Syndrome (DGS) has long been considered the human prototype of a severe T-cell differentiation defect. More recently, the human equivalent of the murine Nude/SCID has been described, contributing to unravel important issues of the T-cell ontogeny in humans. Both mice and human diseases are due to alterations of the FOXN1, a developmentally regulated transcription factor selectively expressed in skin and thymic epithelia.

Romano, Rosa; Palamaro, Loredana; Fusco, Anna; Iannace, Leucio; Maio, Stefano; Vigliano, Ilaria; Giardino, Giuliana; Pignata, Claudio

2012-01-01

185

From murine to human nude/SCID: the thymus, T-cell development and the missing link.  

PubMed

Primary immunodeficiencies (PIDs) are disorders of the immune system, which lead to increased susceptibility to infections. T-cell defects, which may affect T-cell development/function, are approximately 11% of reported PIDs. The pathogenic mechanisms are related to molecular alterations not only of genes selectively expressed in hematopoietic cells but also of the stromal component of the thymus that represents the primary lymphoid organ for T-cell differentiation. With this regard, the prototype of athymic disorders due to abnormal stroma is the Nude/SCID syndrome, first described in mice in 1966. In man, the DiGeorge Syndrome (DGS) has long been considered the human prototype of a severe T-cell differentiation defect. More recently, the human equivalent of the murine Nude/SCID has been described, contributing to unravel important issues of the T-cell ontogeny in humans. Both mice and human diseases are due to alterations of the FOXN1, a developmentally regulated transcription factor selectively expressed in skin and thymic epithelia. PMID:22474479

Romano, Rosa; Palamaro, Loredana; Fusco, Anna; Iannace, Leucio; Maio, Stefano; Vigliano, Ilaria; Giardino, Giuliana; Pignata, Claudio

2012-01-01

186

Comparison of BIOMED-2 Versus Laboratory-Developed Polymerase Chain Reaction Assays for Detecting T-Cell Receptor-? Gene Rearrangements  

PubMed Central

Detecting clonal T-cell receptor (TCR)-? gene rearrangements (GRs) is an important adjunct test for diagnosing T-cell lymphoma. We compared a recently described assay (BIOMED-2 protocol), which targets multiple variable (V) gene segments in two polymerase chain reaction (PCR) reactions (multi-V), with a frequently referenced assay that targets a single V gene segment in four separate PCR reactions (mono-V). A total of 144 consecutive clinical DNA samples were prospectively tested for T-cell clonality by PCR using laboratory-developed mono-V and commercial multi-V primer sets for TCR-? GR. The combination of TCR-?, mono-V TCR-? and multi-V TCR-? detected more clonal cases (68/144, 47%) than any individual PCR assay. We detected clonal TCR-? GR in 47/68 (69%) cases. Using either mono-V or multi-V TCR-? primers, the sensitivities for detecting clonality were 52/68 (76%) or 51/68 (75%). Using both mono-V and multi-V TCR-? primers improved the sensitivity for detecting clonality, 60/68 (88%). Combining either mono-V or multi-V TCR-? primers with TCR-? primers also improved the sensitivity, 64/68 (94%). Significantly, TCR-? V11 GRs could only be detected using the mono-V-PCR primers. We conclude that using more than one T-cell PCR assay can enhance the overall sensitivity for detecting T-cell clonality.

Patel, Keyur P.; Pan, Qiulu; Wang, Yanhua; Maitta, Robert W.; Du, Juan; Xue, Xiaonan; Lin, Juan; Ratech, Howard

2010-01-01

187

A retinoic acid-dependent checkpoint in the development of CD4+ T cell-mediated immunity.  

PubMed

It is known that vitamin A and its metabolite, retinoic acid (RA), are essential for host defense. However, the mechanisms for how RA controls inflammation are incompletely understood. The findings presented in this study show that RA signaling occurs concurrent with the development of inflammation. In models of vaccination and allogeneic graft rejection, whole body imaging reveals that RA signaling is temporally and spatially restricted to the site of inflammation. Conditional ablation of RA signaling in T cells significantly interferes with CD4(+) T cell effector function, migration, and polarity. These findings provide a new perspective of the role of RA as a mediator directly controlling CD4(+) T cell differentiation and immunity. PMID:21859847

Pino-Lagos, Karina; Guo, Yanxia; Brown, Chrysothemis; Alexander, Matthew P; Elgueta, Raúl; Bennett, Kathryn A; De Vries, Victor; Nowak, Elizabeth; Blomhoff, Rune; Sockanathan, Shanthini; Chandraratna, Roshantha A; Dmitrovsky, Ethan; Noelle, Randolph J

2011-08-29

188

An islet-homing NOD CD8 +cytotoxic T cell clone recognizes GAD 65and causes insulitis  

Microsoft Academic Search

T cells play a central role in the development of diabetes both in man and in the non-obese diabetic (NOD) mouse. Both the CD4+and CD8+subsets of T cells are required for the normal development of IDDM in NOD mice. Islet reactive CD4+T cells play a clear pathogenic role as evidenced from the isolation of diabetogenic CD4+T cell clones. CD8+T cells

Nicoline Videbæk; Silvia Harach; Jenny Phillips; Patricia Hutchings; Patricia Ozegbe; Birgitte K Michelsen; Anne Cooke

2003-01-01

189

Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response  

PubMed Central

Programmed cell death 1 (PD-1) is an inhibitory coreceptor on immune cells and is essential for self-tolerance because mice genetically lacking PD-1 (PD-1?/?) develop spontaneous autoimmune diseases. PD-1?/? mice are also susceptible to severe experimental autoimmune encephalomyelitis (EAE), characterized by a massive production of effector/memory T cells against myelin autoantigen, the mechanism of which is not fully understood. We found that an increased primary response of PD-1?/? mice to heat-killed mycobacteria (HKMTB), an adjuvant for EAE, contributed to the enhanced production of T-helper 17 (Th17) cells. Splenocytes from HKMTB-immunized, lymphocyte-deficient PD-1?/? recombination activating gene (RAG)2?/? mice were found to drive antigen-specific Th17 cell differentiation more efficiently than splenocytes from HKMTB-immunized PD-1+/+ RAG2?/? mice. This result suggested PD-1’s involvement in the regulation of innate immune responses. Mice reconstituted with PD-1?/? RAG2?/? bone marrow and PD-1+/+ CD4+ T cells developed more severe EAE compared with the ones reconstituted with PD-1+/+ RAG2?/? bone marrow and PD-1+/+ CD4+ T cells. We found that upon recognition of HKMTB, CD11b+ macrophages from PD-1?/? mice produced very high levels of IL-6, which helped promote naive CD4+ T-cell differentiation into IL-17–producing cells. We propose a model in which PD-1 negatively regulates antimycobacterial responses by suppressing innate immune cells, which in turn prevents autoreactive T-cell priming and differentiation to inflammatory effector T cells.

Rui, Yuxiang; Honjo, Tasuku; Chikuma, Shunsuke

2013-01-01

190

Defective CD8 T Cell Memory Following Acute Infection Without CD4 T Cell Help  

NASA Astrophysics Data System (ADS)

The CD8+ cytotoxic T cell response to pathogens is thought to be CD4+ helper T cell independent because infectious agents provide their own inflammatory signals. Mice that lack CD4+ T cells mount a primary CD8 response to Listeria monocytogenes equal to that of wild-type mice and rapidly clear the infection. However, protective memory to a challenge is gradually lost in the former animals. Memory CD8+ T cells from normal mice can respond rapidly, but memory CD8+ T cells that are generated without CD4 help are defective in their ability to respond to secondary encounters with antigen. The results highlight a previously undescribed role for CD4 help in promoting protective CD8 memory development.

Sun, Joseph C.; Bevan, Michael J.

2003-04-01

191

Functional T cell immunodeficiencies (with T cells present).  

PubMed

Severe combined immunodeficiency (SCID) comprises a group of disorders that are fatal owing to genetic defects that abrogate T cell development. Numerous related defects have recently been identified that allow T cell development but that compromise T cell function by affecting proximal or distal steps in intracellular signaling. These functional T cell immunodeficiencies are characterized by immune dysregulation and increased risk of malignancies, in addition to infections. The study of patients with these rare conditions, and of corresponding animal models, illustrates the importance of intracellular signaling to maintain T cell homeostasis. PMID:23298211

Notarangelo, Luigi D

2013-01-01

192

Lipopeptides of Borrelia burgdorferi outer surface proteins induce Th1 phenotype development in alphabeta T-cell receptor transgenic mice.  

PubMed Central

Induction of the appropriate T helper cell (Th) subset is crucial for the resolution of infectious diseases and the prevention of immunopathology. Some pathogens preferentially induce Th1 or Th2 responses. How microorganisms influence Th phenotype development is unknown. We asked if Borrelia burgdorferi, the spirochete which causes Lyme arthritis, can promote a cytokine milieu in which T cells which are not specific for B. burgdorferi are induced to produce proinflammatory cytokines. Using alphabeta T-cell receptor transgenic mice as a source of T cells with a defined specificity other than for B. burgdorferi, we found that B. burgdorferi induced Th1 phenotype development in ovalbumin-specific transgenic T cells. Small synthetic lipopeptides corresponding to the N-terminal sequences of B. burgdorferi outer surface lipoproteins had similar effects. B. burgdorferi and its lipopeptides induced host cells to produce interleukin-12. When the peptides were used in delipidated form, they did not induce Th1 development. These findings may be of pathogenic importance, since it is currently assumed that a Th2-mediated antibody response is protective against B. burgdorferi. Bacteria associated with reactive arthritis, namely, Yersinia enterocolitica, Shigella flexneri, and Salmonella enteritidis, had different effects. The molecular definition of pathogen-host interactions determining cytokine production should facilitate rational therapeutic interventions directing the host response towards the desired cytokine response. Here, we describe small synthetic molecules capable of inducing Th1 phenotype development.

Infante-Duarte, C; Kamradt, T

1997-01-01

193

Flow-cytometric measurement of CD4(sup -)8(sup -) T cells bearing T-cell receptor (alpha)(beta) chains, 1. Results for a normal population including two cases with unusually high frequencies.  

National Technical Information Service (NTIS)

In this study we detected rare, possibly abnormal, T cells bearing CD3 surface antigen and T-cell receptor (TCR) (alpha)(beta) chains but lacking both CD4 and CD8 antigens (viz., TCR(alpha)(beta)(sup +)CD4(sup -)8(sup -) cells, as determined by flow cytom...

Y. Kusunoki Y. Hirai S. Kyoizumi M. Akiyama

1992-01-01

194

Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells.  

PubMed

The cytokines controlling the development of human interleukin (IL) 17--producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17--producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) beta, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17--producing T cells. These data suggest that IL-12Rbeta1- and STAT-3--dependent signals play a key role in the differentiation and/or expansion of human IL-17-producing T cell populations in vivo. PMID:18591412

de Beaucoudrey, Ludovic; Puel, Anne; Filipe-Santos, Orchidée; Cobat, Aurélie; Ghandil, Pegah; Chrabieh, Maya; Feinberg, Jacqueline; von Bernuth, Horst; Samarina, Arina; Jannière, Lucile; Fieschi, Claire; Stéphan, Jean-Louis; Boileau, Catherine; Lyonnet, Stanislas; Jondeau, Guillaume; Cormier-Daire, Valérie; Le Merrer, Martine; Hoarau, Cyrille; Lebranchu, Yvon; Lortholary, Olivier; Chandesris, Marie-Olivia; Tron, François; Gambineri, Eleonora; Bianchi, Lucia; Rodriguez-Gallego, Carlos; Zitnik, Simona E; Vasconcelos, Julia; Guedes, Margarida; Vitor, Artur Bonito; Marodi, Laszlo; Chapel, Helen; Reid, Brenda; Roifman, Chaim; Nadal, David; Reichenbach, Janine; Caragol, Isabel; Garty, Ben-Zion; Dogu, Figen; Camcioglu, Yildiz; Gülle, Sanyie; Sanal, Ozden; Fischer, Alain; Abel, Laurent; Stockinger, Birgitta; Picard, Capucine; Casanova, Jean-Laurent

2008-07-01

195

Development of a T Cell Receptor Targeting an HLA-A*0201 Restricted Epitope from the Cancer-Testis Antigen SSX2 for Adoptive Immunotherapy of Cancer  

PubMed Central

The clinical success of adoptive immunotherapy of cancer relies on the selection of target antigens that are highly expressed in tumor cells but absent in essential normal tissues. A group of genes that encode the cancer/testis or cancer germline antigens have been proposed as ideal targets for immunotherapy due to their high expression in multiple cancer types and their restricted expression in immunoprivileged normal tissues. In the present work we report the isolation and characterization of human T cell receptors (TCRs) with specificity for synovial sarcoma X breakpoint 2 (SSX2), a cancer/testis antigen expressed in melanoma, prostate cancer, lymphoma, multiple myeloma and pancreatic cancer, among other tumors. We isolated seven HLA-A2 restricted T cell receptors from natural T cell clones derived from tumor-infiltrated lymph nodes of two SSX2-seropositive melanoma patients, and selected four TCRs for cloning into retroviral vectors. Peripheral blood lymphocytes (PBL) transduced with three of four SSX2 TCRs showed SSX241-49 (KASEKIFYV) peptide specific reactivity, tumor cell recognition and tetramer binding. One of these, TCR-5, exhibited tetramer binding in both CD4 and CD8 cells and was selected for further studies. Antigen-specific and HLA-A*0201-restricted interferon-? release, cell lysis and lymphocyte proliferation was observed following culture of TCR engineered human PBL with relevant tumor cell lines. Codon optimization was found to increase TCR-5 expression in transduced T cells, and this construct has been selected for development of clinical grade viral vector producing cells. The tumor-specific pattern of expression of SSX2, along with the potent and selective activity of TCR-5, makes this TCR an attractive candidate for potential TCR gene therapy to treat multiple cancer histologies.

Abate-Daga, Daniel; Speiser, Daniel E.; Chinnasamy, Nachimuthu; Zheng, Zhili; Xu, Hui; Feldman, Steven A.; Rosenberg, Steven A.; Morgan, Richard A.

2014-01-01

196

T cells as therapeutic targets in SLE  

PubMed Central

T cells contribute to the initiation and perpetuation of autoimmunity in systemic lupus erythematosus (SLE), and seem to be directly involved in the development of related organ pathology. Defects associated with CD8+ and T-regulatory (TREG) cell function manifest in parallel with the expanded CD3+CD4?CD8? T cell lineage. The cytokine expression pattern is uniquely characterized by decreased expression of interleukin (IL)-2 and increased production of IL-17 and related cytokines. Therapeutic approaches that limit the cognate interaction between T cells and B cells, prevent inappropriate tissue homing and restore TREG cell function and the normal cytokine milieu have been entertained. Biochemical characterization of SLE T cells has revealed distinct early and late signaling aberrations, and has enabled the identification of novel molecular targets that can be corrected with small molecules, and biomarkers that may foretell disease activity and predict organ damage.

Crispin, Jose C.; Kyttaris, Vasileios C.; Terhorst, Cox; Tsokos, George C.

2010-01-01

197

Requirement for Notch1 signals at sequential early stages of intrathymic T cell development  

Microsoft Academic Search

Signaling through the transmembrane Notch1 receptor directs thymus-seeding progenitors (TSPs) to suppress their B cell potential and 'choose' the T cell fate. Present paradigms suggest that TSPs are contained in the multipotent early T lineage precursor (ETP) subset of thymocytes. However, we show here that the B cell potential of ETPs was not augmented in microenvironments that limited Notch1 activation.

Joanne B Tan; Ioana Visan; Julie S Yuan; Cynthia J Guidos

2005-01-01

198

Dissecting the Mechanisms of T Cell Tolerance for More Effective Breast Cancer Vaccine Development.  

National Technical Information Service (NTIS)

T cell tolerance to tumor-associated antigens is a significant barrier to immune based treatments of human cancers. One such tumor-associated antigen is the proto-oncogene HER-2/neu (neu) which is overexpressed in 35-40% of all human breast cancers. Altho...

B. H. Ladle E. M. Jaffee

2003-01-01

199

Differential requirements of CD4+ T-cell signals for effector cytotoxic T-lymphocyte (CTL) priming and functional memory CTL development at higher CD8+ T-cell precursor frequency  

PubMed Central

Increased CD8+ T-cell precursor frequency (PF) precludes the requirement of CD4+ helper T (Th) cells for primary CD8+ cytotoxic T-lymphocyte (CTL) responses. However, the key questions of whether unhelped CTLs generated at higher PF are functional effectors, and whether unhelped CTLs can differentiate into functional memory cells at higher PF are unclear. In this study, ovalbumin (OVA) -pulsed dendritic cells (DCOVA) derived from C57BL/6, CD40 knockout (CD40?/?) or CD40 ligand knockout (CD40L?/?) mice were used to immunize C57BL/6, Iab?/?, CD40?/? or CD40L?/? mice, whose PF was previously increased with transfer of 1 × 106 CD8+ T cells derived from OVA-specific T-cell receptor (TCR) transgenic OTI, OTI(CD40?/?) or OTI(CD40L?/?) mice. All the immunized mice were then assessed for effector and memory CTL responses. Following DC immunization, relatively comparable CTL priming occurred without CD4+ T-cell help and Th-provided CD40/CD40L signalling. In addition, the unhelped CTLs were functional effectors capable of inducing therapeutic immunity against established OVA-expressing tumours. In contrast, the functional memory development of CTLs was severely impaired in the absence of CD4+ T-cell help and CD40/CD40L signalling. Finally, unhelped memory CTLs failed to protect mice against lethal tumour challenge. Taken together, these results demonstrate that CD4+ T-cell help at higher PF, is not required for effector CTL priming, but is required for functional memory CTL development against cancer. Our data may impact the development of novel preventive and therapeutic approaches in cancer patients with compromised CD4+ T-cell functions.

Umeshappa, Channakeshava S; Nanjundappa, Roopa H; Xie, Yufeng; Freywald, Andrew; Xu, Qingyong; Xiang, Jim

2013-01-01

200

Retinoic acids exert direct effects on T cells to suppress Th1 development and enhance Th2 development via retinoic acid receptors  

Microsoft Academic Search

The vitamin A metabolite, retinoic acid (RA), affects Th1 and Th2 development. The effect is partly exerted through the modulation of antigen-presenting cell functions, but it remains unclear whether RA directly exerts its effect on T cells to influence Th1\\/Th2 development. To clarify this problem, we used two experimental systems with isolated T cells in vitro. In one system, isolated

Makoto Iwata; Yuko Eshima; Hiroyuki Kagechika

2003-01-01

201

CARMA1 controls an early checkpoint in the thymic development of FoxP3+ regulatory T cells  

PubMed Central

Natural regulatory T cells (nTregs) that develop in the thymus are essential to limit immune responses and prevent autoimmunity. However, the steps necessary for their thymic development are incompletely understood. The CARMA1/Bcl10/Malt1 (CBM) complex, comprised of adaptors that link the TCR to the transcription factor NF-?B, is required for development of Tregs but not of conventional T cells. Current models propose that TCR-NF-?B is needed in a Treg-extrinsic manner for IL-2 production by conventional T cells or in already pre-committed Treg precursors for driving IL-2/STAT5 responsiveness and further maturation into Tregs and/or for promoting cell survival. Using CARMA1-KO mice, our data show instead that the CBM complex is needed in a Treg-intrinsic rather than extrinsic manner. Constitutive activity of STAT5 or protection from apoptosis by transgenic expression of Bcl2 in developing Tregs is not sufficient to rescue CARMA1-KO Treg development. Instead, our results demonstrate that the CBM complex controls an early checkpoint in Treg development by enabling generation of thymic precursors of Tregs. These data suggest a modified model of nTreg development in which TCR-CBM-dependent signals are essential to commit immature thymocytes to the nTreg lineage.

Molinero, Luciana L; Yang, Jianying; Gajewski, Thomas; Abraham, Clara; Farrar, Michael A; Alegre, Maria-Luisa

2010-01-01

202

A role for apoptosis-inducing factor in T cell development  

PubMed Central

Apoptosis-inducing factor (Aif) is a mitochondrial flavoprotein that regulates cell metabolism and survival in many tissues. We report that aif-hypomorphic harlequin (Hq) mice show thymic hypocellularity and a cell-autonomous thymocyte developmental block associated with apoptosis at the ?-selection stage, independent of T cell receptor ? recombination. No abnormalities are observed in the B cell lineage. Transgenes encoding wild-type or DNA-binding–deficient mutant Aif rectify the thymic defect, but a transgene encoding oxidoreductase activity–deficient mutant Aif does not. The Hq thymic block is reversed in vivo by antioxidant treatment, and Hq T but not B lineage cells show enhanced oxidative stress. Thus, Aif, a ubiquitous protein, serves a lineage-specific nonredundant antiapoptotic role in the T cell lineage by regulating reactive oxygen species during thymic ?-selection.

Banerjee, Hridesh; Das, Abhishek; Srivastava, Smita; Mattoo, Hamid R.; Thyagarajan, Krishnamurthy; Khalsa, Jasneet Kaur; Tanwar, Shalini; Das, Deepika Sharma; Majumdar, Subeer S.; George, Anna; Bal, Vineeta; Durdik, Jeannine M.

2012-01-01

203

IL2 Receptor Dependent STAT5 Activation Is Required for the Development of Foxp3 Regulatory T Cells1  

Microsoft Academic Search

egulatory T cells (Tregs)4 have recently been the subject of intense research due to their critical role in preventing autoimmune disease. However, the molecular factors that regulate the development, homeostasis, and function of Tregs re- main to be fully elucidated. Previous studies have demonstrated that the loss of IL-2, IL-2R, or IL-2R leads to the unexpected development of lethal autoimmune

Matthew A. Burchill; Jianying Yang; Christine Vogtenhuber; Bruce R. Blazar; Michael A. Farrar

204

The orphan nuclear receptor Ear-2 (Nr2f6) is a novel negative regulator of T cell development.  

PubMed

We describe a novel role for the orphan nuclear receptor Ear-2 in regulating T cell development. Retrovirus-mediated overexpression of Ear-2 (EAR-2++) in a bone marrow (BM) transplantation assay resulted in limited T cell development and a greater than tenfold decrease in thymus size and cellularity relative to controls. Ear-2-transduced murine BM hematopoietic stem cells (HSCs) in OP9-DL1 cultures showed a proliferation deficit during days 1-5 after induction of differentiation, which corresponded to increased expression of the cell cycle regulators p21 (cdkn1a) and p27 (cdkn1b), as well as increased expression of Hes1, Notch3, Egr1, and Scl (Tal1) and decreased expression of Gli1, Gfi-1, HoxA9, PU.1, Nrarp, and Tcf1. In addition, there was a block in differentiation at the DN4 to double-positive (DP) transition accompanied by an increase in apoptosis, similar to the deficit seen in the ROR?t null mouse. Gene expression profiling revealed that, like the ROR?t-deficient mouse, EAR-2++ DP cells had decreased expression of BclXL and increased expression of the proapoptosis gene Bad. In addition, EAR-2++ DP cells had decreased expression of Bcl11b, PU.1, and HoxA9, and increased expression of Id2. Based on these findings, we conclude that EAR-2++ cells were able to migrate to, but not fully repopulate, the thymus because of a cell-intrinsic defect in the proliferation of DN1 cells followed by a block in differentiation from the DN4 to DP stage of T cell development. We conclude that Ear-2 is a novel negative regulator of T-cell development and that downregulation of Ear-2 is indispensable for the proliferation of DN1 cells and the survival of DN4-DP cells. PMID:24096122

Ichim, Christine V; Dervovi?, Džana D; Zúñiga-Pflücker, Juan Carlos; Wells, Richard A

2014-01-01

205

The Nuclear Effector of Wnt-Signaling, Tcf1, Functions as a T-Cell-Specific Tumor Suppressor for Development of Lymphomas  

PubMed Central

The HMG-box factor Tcf1 is required during T-cell development in the thymus and mediates the nuclear response to Wnt signals. Tcf1?/? mice have previously been characterized and show developmental blocks at the CD4?CD8? double negative (DN) to CD4+CD8+ double positive transition. Due to the blocks in T-cell development, Tcf1?/? mice normally have a very small thymus. Unexpectedly, a large proportion of Tcf1?/? mice spontaneously develop thymic lymphomas with 50% of mice developing a thymic lymphoma/leukemia at the age of 16 wk. These lymphomas are clonal, highly metastatic, and paradoxically show high Wnt signaling when crossed with Wnt reporter mice and have high expression of Wnt target genes Lef1 and Axin2. In wild-type thymocytes, Tcf1 is higher expressed than Lef1, with a predominance of Wnt inhibitory isoforms. Loss of Tcf1 as repressor of Lef1 leads to high Wnt activity and is the initiating event in lymphoma development, which is exacerbated by activating Notch1 mutations. Thus, Notch1 and loss of Tcf1 functionally act as collaborating oncogenic events. Tcf1 deficiency predisposes to the development of thymic lymphomas by ectopic up-regulation of Lef1 due to lack of Tcf1 repressive isoforms and frequently by cooperating activating mutations in Notch1. Tcf1 therefore functions as a T-cell–specific tumor suppressor gene, besides its established role as a Wnt responsive transcription factor. Thus, Tcf1 acts as a molecular switch between proliferative and repressive signals during T-lymphocyte development in the thymus.

Tiemessen, Machteld M.; Baert, Miranda R. M.; Schonewille, Tom; Brugman, Martijn H.; Famili, Farbod; Salvatori, Daniela C. F.; Meijerink, Jules P. P.; Ozbek, Ugur; Clevers, Hans; van Dongen, Jacques J. M.; Staal, Frank J. T.

2012-01-01

206

Development of Notch-dependent T-cell leukemia by deregulated Rap1 signaling.  

PubMed

SPA-1 (signal-induced proliferation associated gene-1) functions as a suppressor of myeloid leukemia by negatively regulating Rap1 signaling in hematopoietic progenitor cells (HPCs). Herein, we showed that transplantation of HPCs expressing farnesylated C3G (C3G-F), a Rap1 guanine nucleotide exchange factor, resulted in a marked expansion of thymocytes bearing unique phenotypes (CD4/CD8 double positive [DP] CD3(-) TCRbeta(-)) in irradiated recipients. SPA-1(-/-) HPCs expressing C3G-F caused a more extensive expansion of DP thymocytes, resulting in lethal T-cell acute lymphoblastic leukemia (T-ALL) with massive invasion of clonal T-cell blasts into vital organs. The C3G-F(+) blastic thymocytes exhibited constitutive Rap1 activation and markedly enhanced expression of Notch1, 3 as well as the target genes, Hes1, pTalpha, and c-Myc. All the T-ALL cell lines from C3G-F(+) SPA-1(-/-) HPC recipients expressed high levels of Notch1 with characteristic mutations resulting in the C-terminal truncation. This proliferation was inhibited completely in the presence of a gamma-secretase inhibitor. Transplantation of Rag2(-/-) SPA-1(-/-) HPCs expressing C3G-F also resulted in a marked expansion and transformation of DP thymocytes. The results suggested that deregulated constitutive Rap1 activation caused abnormal expansion of DP thymocytes, bypassing the pre-T-cell receptor and eventually leading to Notch1 mutations and Notch-dependent T-ALL. PMID:18180377

Wang, Shu-Fang; Aoki, Misayo; Nakashima, Yasuhiro; Shinozuka, Yoriko; Tanaka, Hiroki; Taniwaki, Masafumi; Hattori, Masakazu; Minato, Nagahiro

2008-03-01

207

Normal growth and development  

MedlinePLUS

... and development can be divided into four periods: Infancy Preschool years Middle childhood years Adolescence Immediately after ... enough nutrition. Healthy eating habits should begin during infancy to prevent diseases such as type 2 diabetes, ...

208

Identification of stem cell transcriptional programs normally expressed in embryonic and neural stem cells in alloreactive CD8+ T cells mediating graft-versus-host disease  

PubMed Central

A hallmark of graft-versus-host-disease (GVHD), a life-threatening complication after allogeneic hematopoietic stem cell transplantation, is the cytopathic injury of host tissues mediated by persistent alloreactive effector T cells (TE). However, the mechanisms that regulate the persistence of alloreactive TE during GVHD remain largely unknown. Using mouse GVHD models, we demonstrate that alloreactive CD8+ TE rapidly diminished in vivo when adoptively transferred into irradiated secondary congenic recipient mice. In contrast, although alloreactive CD8+ TE underwent massive apoptosis upon chronic exposure to alloantigens, they proliferated in vivo in secondary allogeneic recipients, persisted and caused severe GVHD. Thus, the continuous proliferation of alloreactive CD8+ TE, which is mediated by alloantigenic stimuli rather than homeostatic factors, is critical to maintaining their persistence. Gene expression profile analysis revealed that while alloreactive CD8+ TE increased the expression of genes associated with cell death, they activated a group of stem cell genes normally expressed in embryonic and neural stem cells. Most of these stem cell genes are associated with cell cycle regulation, DNA replication, chromatin modification and transcription. One of these genes, Ezh2, which encodes a chromatin modifying enzyme, was abundantly expressed in CD8+ TE. Silencing Ezh2 significantly reduced the proliferation of alloantigen-activated CD8+ T cells. Thus, these findings identify that a group of stem cell genes could play important roles in sustaining terminally differentiated alloreactive CD8+ TE and may be therapeutic targets for controlling GVHD.

Kato, Koji; Cui, Shuaiying; Kuick, Rork; Mineishi, Shin; Hexner, Elizabeth; Ferrara, James LM; Emerson, Stephen G.; Zhang, Yi

2010-01-01

209

The ? isoform of diacylglycerol kinase plays a predominant role in regulatory T cell development and TCR-mediated ras signaling.  

PubMed

Diacylglycerol (DAG) is a critical second messenger that mediates T cell receptor (TCR)-stimulated signaling. The abundance of DAG is reduced by the diacylglycerol kinases (DGKs), which catalyze the conversion of DAG to phosphatidic acid (PA) and thus inhibit DAG-mediated signaling. In T cells, the predominant DGK isoforms are DGK? and DGK?, and deletion of the genes encoding either isoform enhances DAG-mediated signaling. We found that DGK?, but not DGK?, suppressed the development of natural regulatory T (T(reg)) cells and predominantly mediated Ras and Akt signaling downstream of the TCR. The differential functions of DGK? and DGK? were not attributable to differences in protein abundance in T cells or in their localization to the contact sites between T cells and antigen-presenting cells. RasGRP1, a key DAG-mediated activator of Ras signaling, associated to a greater extent with DGK? than with DGK?; however, in silico modeling of TCR-stimulated Ras activation suggested that a difference in RasGRP1 binding affinity was not sufficient to cause differences in the functions of each DGK isoform. Rather, the model suggested that a greater catalytic rate for DGK? than for DGK? might lead to DGK? exhibiting increased suppression of Ras-mediated signals compared to DGK?. Consistent with this notion, experimental studies demonstrated that DGK? was more effective than DGK? at catalyzing the metabolism of DAG to PA after TCR stimulation. The enhanced effective enzymatic production of PA by DGK? is therefore one possible mechanism underlying the dominant functions of DGK? in modulating T(reg) cell development. PMID:24280043

Joshi, Rohan P; Schmidt, Amanda M; Das, Jayajit; Pytel, Dariusz; Riese, Matthew J; Lester, Melissa; Diehl, J Alan; Behrens, Edward M; Kambayashi, Taku; Koretzky, Gary A

2013-01-01

210

E3 ubiquitin ligase Cbl-b suppresses proallergic T cell development and allergic airway inflammation.  

PubMed

E3 ubiquitin ligase Cbl-b has emerged as a gatekeeper that controls the activation threshold of the T cell antigen receptor and maintains the balance between tolerance and autoimmunity. Here, we report that the loss of Cbl-b facilitates T helper 2 (Th2) and Th9 cell differentiation in vitro. In a mouse model of asthma, the absence of Cbl-b results in severe airway inflammation and stronger Th2 and Th9 responses. Mechanistically, Cbl-b selectively associates with Stat6 upon IL-4 ligation and targets Stat6 for ubiquitination and degradation. These processes are heightened in the presence of T cell receptor (TCR)/CD28 costimulation. Furthermore, we identify K108 and K398 as Stat6 ubiquitination sites. Intriguingly, introducing Stat6 deficiency into Cblb(-/-) mice abrogates hyper-Th2 responses but only partially attenuates Th9 responses. Therefore, our data reveal a function for Cbl-b in the regulation of Th2 and Th9 cell differentiation. PMID:24508458

Qiao, Guilin; Ying, Haiyan; Zhao, Yixia; Liang, Yanran; Guo, Hui; Shen, Huifeng; Li, Zhenping; Solway, Julian; Tao, Enxiang; Chiang, Y Jeffrey; Lipkowitz, Stanley; Penninger, Josef M; Langdon, Wallace Y; Zhang, Jian

2014-02-27

211

Regulation of intrathymic T-cell development by Lunatic Fringe- Notch1 interactions.  

PubMed

Intrathymic Notch1 signaling critically regulates T-lineage specification and commitment as well as T-cell progenitor survival and differentiation. Notch1 activation is continuously required during progression of early CD4/CD8-double-negative thymocytes to the CD4/CD8-double-positive stage. This developmental transition occurs as thymocytes migrate from the corticomedullary junction (CMJ) to the outer subcapsular zone (SCZ) of the thymus. Members of two families of structurally distinct Notch ligands, Delta-like 1 and Jagged-1, are expressed by cortical thymic epithelial cells, but it is not known which ligands are functionally required within the CMJ and SCZ microenvironmental niches. Our laboratory has investigated this question by genetically manipulating thymocyte expression of Lunatic Fringe (L-Fng), a glycosyltransferase that enhances sensitivity of Notch receptors to Delta-like ligands. This approach has revealed that low-threshold intrathymic Notch1 signals instruct multipotent thymus-seeding progenitors to suppress their B-cell potential and choose the T-cell fate. This strategy has also revealed that Delta-like Notch ligands are functionally limiting in both the CMJ and SCZ microenvironmental niches. Finally, we discuss our recent demonstration that L-Fng-mediated competition for Delta-like ligands is an important mechanism for regulating thymus size. PMID:16448535

Visan, Ioana; Yuan, Julie S; Tan, Joanne B; Cretegny, Kira; Guidos, Cynthia J

2006-02-01

212

IL-27 inhibits the development of regulatory T cells via STAT3.  

PubMed

Regulatory CD4+ T cells are important for the homeostasis of the immune system and their absence correlates with autoimmune disorders. Here, we investigate the capacity of IL-27, a cytokine with pro- and anti-inflammatory properties, to regulate the generation of transforming growth factor beta (TGFbeta)-inducible forkhead box P3 (Foxp3)-positive regulatory T (Treg) cells. Our results demonstrate that IL-27 inhibits the acquisition of the Treg phenotype at the level of Foxp3, CD25 and CTLA-4 (CD152) expression as well as the suppressive function. In contrast to TGFbeta-induced Treg cells, the cells generated after differentiation in the presence of TGFbeta and IL-27 maintained the ability for IL-2 and tumour necrosis factor alpha (TNFalpha) production. The inhibitory effect of IL-27 on Treg generation was at least partially signal transducer and activator of transcription 3 (STAT3) dependent as examined by targeted STAT3 protein inhibition using small interfering RNA (siRNA), while STAT1-dependent signals seemed to oppose the STAT3 signals. In turn, TGFbeta blocked IL-27-induced T(h)1 differentiation. Thus, IL-27 and TGFbeta mutually control their effects on CD4+ T-cell differentiation, whereby IL-27 favours inflammatory conditions through a STAT3-dependent inhibition of Treg generation. PMID:18156621

Huber, Magdalena; Steinwald, Vera; Guralnik, Anna; Brüstle, Anne; Kleemann, Peter; Rosenplänter, Christine; Decker, Thomas; Lohoff, Michael

2008-02-01

213

Development of memory CD8+ T cells and their recall responses during blood-stage infection with Plasmodium berghei ANKA.  

PubMed

Conditions required for establishing protective immune memory vary depending on the infecting microbe. Although the memory immune response against malaria infection is generally thought to be relatively slow to develop and can be lost rapidly, experimental evidence is insufficient. In this report, we investigated the generation, maintenance, and recall responses of Ag-specific memory CD8(+) T cells using Plasmodium berghei ANKA expressing OVA (PbA-OVA) as a model system. Mice were transferred with OVA-specific CD8(+) T (OT-I) cells and infected with PbA-OVA or control Listeria monocytogenes expressing OVA (LM-OVA). Central memory type OT-I cells were maintained for >2 mo postinfection and recovery from PbA-OVA. Memory OT-I cells produced IFN-? as well as TNF-? upon activation and were protective against challenge with a tumor expressing OVA, indicating that functional memory CD8(+) T cells can be generated and maintained postinfection with P. berghei ANKA. Cotransfer of memory OT-I cells with naive OT-I cells to mice followed by infection with PbA-OVA or LM-OVA revealed that clonal expansion of memory OT-I cells was limited during PbA-OVA infection compared with expansion of naive OT-I cells, whereas it was more rapid during LM-OVA infection. The expression of inhibitory receptors programmed cell death-1 and LAG-3 was higher in memory-derived OT-I cells than naive-derived OT-I cells during infection with PbA-OVA. These results suggest that memory CD8(+) T cells can be established postinfection with P. berghei ANKA, but their recall responses during reinfection are more profoundly inhibited than responses of naive CD8(+) T cells. PMID:23008449

Miyakoda, Mana; Kimura, Daisuke; Honma, Kiri; Kimura, Kazumi; Yuda, Masao; Yui, Katsuyuki

2012-11-01

214

Hierarchical self-tolerance to T cell determinants within the ubiquitous nuclear self-antigen La (SS-B) permits induction of systemic autoimmunity in normal mice  

PubMed Central

Systemic autoimmune diseases are frequently associated with clustering of high titer autoantibody responses towards nuclear self-antigens. Little is known, however, about the extent of immune tolerance to the target nuclear antigens or the events leading to the complex autoantibody responses that are characteristic of systemic autoimmunity. To address these issues, we have examined the mouse immune response to La autoantigen (mLa) and the homologous human La antigen (hLa), which are components of the La(SS-B)/Ro(SS-A) ribonucleoprotein (RNP) complex targeted in systemic lupus erythematosus and primary Sjogren's syndrome. The findings reveal the presence of hierarchical T cell tolerance involving multiple autodeterminants within the La autoantigen expressed by normal H-2k and H-2a mice. At one end of this spectrum, there was no detectable T or B cell autoimmunity observed in mice that were immunized with the immunodominant mLa287-301 determinant, which differed by a single residue in its core sequence from the homologous but highly immunogenic human La288-302 determinant. Interestingly, the mLa287-301 peptide acted as an altered peptide ligand that specifically antagonized the activation of an hLa288-302-specific T cell hybridoma. In contrast to the tolerogenic mLa287-301 determinant, a range of autoimmune potential was identified among poorly tolerizing, subdominant self-peptides present within mouse La autoantigen. Notably, immunization of normal mice with the autologous subdominant La25-44 and La106-129 determinants resulted in limited or no detectable autoantibody response. In contrast, immunization with the subdominant mouse La13-30 determinant induced a proliferative T cell response associated with the appearance of specific autoantibodies recognizing multiple intrastructural (La) and intermolecular components (Ro) of the murine La/Ro RNP. The findings suggest how diversified autoimmunity might follow initiation of immunity to simple peptide mimics of poorly tolerogenic determinants that are present within ubiquitous self-antigens.

1996-01-01

215

T Cells and Adoptive Immunotherapy: Recent Developments and Future Prospects in Gastrointestinal Oncology  

PubMed Central

Gastrointestinal oncology is one of the foremost causes of death: the gastric cancer accounts for 10.4% of cancer deaths worldwide, the pancreatic cancer for 6%, and finally, the colorectal cancer for 9% of all cancer-related deaths. For all these gastrointestinal cancers, surgical tumor resection remains the primary curative treatment, but the overall 5-year survival rate remains poor, ranging between 20–25%; the addition of combined modality strategies (pre- or postoperative chemoradiotherapy or perioperative chemotherapy) results in 5-year survival rates of only 30–35%. Therefore, many investigators believe that the potential for making significant progress lies on understanding and exploiting the molecular biology of gastrointestinal tumors to investigate new therapeutic strategies such as specific immunotherapy. In this paper we will focus on recent knowledge concerning the role of T cells and the use of T adoptive immunotherapy in the treatment of gastrointestinal cancers.

Amedei, Amedeo; Niccolai, Elena; D'Elios, Mario M.

2011-01-01

216

T cell development requires constraint of the myeloid regulator C/EBPa by the Notch target and transcriptional repressor Hes1  

PubMed Central

Notch signaling induces gene expression of the T cell lineage and discourages alternative fate outcomes. Hematopoietic deficiency in the Notch target Hes1 results in severe T cell lineage defects; however, the underlying mechanism is unknown. We found here that Hes1 constrained myeloid gene-expression programs in T cell progenitor cells, as deletion of the myeloid regulator C/EBPa restored the development of T cells from Hes1-deficient progenitor cells. Repression of Cebpa by Hes1 required its DNA-binding and Groucho-recruitment domains. Hes1-deficient multipotent progenitor cells showed a developmental bias toward myeloid and dendritic cells after Notch signaling, whereas Hes1-deficient lymphoid progenitor cells required additional cytokine signaling for diversion into the myeloid lineage. Our findings establish the importance of constraining developmental programs of the myeloid lineage early in T cell development.

De Obaldia, Maria Elena; Bell, J Jeremiah; Wang, Xinxin; Harly, Christelle; Yashiro-Ohtani, Yumi; DeLong, Jonathan H; Zlotoff, Daniel A; Sultana, Dil Afroz; Pear, Warren S; Bhandoola, Avinash

2014-01-01

217

Recognition of Glioma Stem Cells by Genetically Modified T Cells Targeting EGFRvIII and Development of Adoptive Cell Therapy for Glioma  

PubMed Central

Abstract No curative treatment exists for glioblastoma, with median survival times of less than 2 years from diagnosis. As an approach to develop immune-based therapies for glioblastoma, we sought to target antigens expressed in glioma stem cells (GSCs). GSCs have multiple properties that make them significantly more representative of glioma tumors than established glioma cell lines. Epidermal growth factor receptor variant III (EGFRvIII) is the result of a novel tumor-specific gene rearrangement that produces a unique protein expressed in approximately 30% of gliomas, and is an ideal target for immunotherapy. Using PCR primers spanning the EGFRvIII-specific deletion, we found that this tumor-specific gene is expressed in three of three GCS lines. Based on the sequence information of seven EGFRvIII-specific monoclonal antibodies (mAbs), we assembled chimeric antigen receptors (CARs) and evaluated the ability of CAR-engineered T cells to recognize EGFRvIII. Three of these anti-EGFRvIII CAR-engineered T cells produced the effector cytokine, interferon-?, and lysed antigen-expressing target cells. We concentrated development on a CAR produced from human mAb 139, which specifically recognized GSC lines and glioma cell lines expressing mutant EGFRvIII, but not wild-type EGFR and did not recognize any normal human cell tested. Using the 139-based CAR, T cells from glioblastoma patients could be genetically engineered to recognize EGFRvIII-expressing tumors and could be expanded ex vivo to large numbers, and maintained their antitumor activity. Based on these observations, a ?-retroviral vector expressing this EGFRvIII CAR was produced for clinical application.

Johnson, Laura A.; Davis, Jeremy L.; Zheng, Zhili; Woolard, Kevin D.; Reap, Elizabeth A.; Feldman, Steven A.; Chinnasamy, Nachimuthu; Kuan, Chien-Tsun; Song, Hua; Zhang, Wei; Fine, Howard A.; Rosenberg, Steven A.

2012-01-01

218

Id3 and Id2 act as a dual safety mechanism in regulating the development and population size of innate-like ?? T cells.  

PubMed

The innate-like T cells expressing V?1.1 and V?6.3 represent a unique T cell lineage sharing features with both the ?? T and the invariant NKT cells. The population size of V?1.1(+)V?6.3(+) T cells is tightly controlled and usually contributes to a very small proportion of thymic output, but the underlying mechanism remains enigmatic. Deletion of Id3, an inhibitor of E protein transcription factors, can induce an expansion of the V?1.1(+)V?6.3(+) T cell population. This phenotype is much stronger on the C57BL/6 background than on the 129/sv background. Using quantitative trait linkage analysis, we identified Id2, a homolog of Id3, to be the major modifier of Id3 in limiting V?1.1(+)V?6.3(+) T cell expansion. The V?1.1(+)V?6.3(+) phenotype is attributed to an intrinsic weakness of Id2 transcription from Id2 C57BL/6 allele, leading to an overall reduced dosage of Id proteins. However, complete removal of both Id2 and Id3 genes in developing T cells suppressed the expansion of V?1.1(+)V?6.3(+) T cells because of decreased proliferation and increased cell death. We showed that conditional knockout of Id2 alone is sufficient to promote a moderate expansion of ?? T cells. These regulatory effects of Id2 and Id3 on V?1.1(+)V?6.3(+) T cells are mediated by titration of E protein activity, because removing one or more copies of E protein genes can restore V?1.1(+)V?6.3(+) T cell expansion in Id2 and Id3 double conditional knockout mice. Our data indicated that Id2 and Id3 collaboratively control survival and expansion of the ?? lineage through modulating a proper threshold of E proteins. PMID:24379125

Zhang, Baojun; Lin, Yen-Yu; Dai, Meifang; Zhuang, Yuan

2014-02-01

219

Temporal differences in the dependency on phosphoinositide-dependent kinase 1 distinguish the development of invariant Valpha14 NKT cells and conventional T cells.  

PubMed

This study uses two independent genetic strategies to explore the requirement for phosphoinositide-dependent kinase-1 (PDK1) in the development of mature T cell populations from CD4/CD8 double-positive thymocytes. The data show that CD4/CD8 double-positive thymocytes that do not express PDK1 or express a catalytically inactive PDK1 mutant fail to produce mature invariant V?14 NKT cells but can differentiate to conventional CD4, CD8, or regulatory T cell subsets in the thymus. The PDK1 requirement for V?14 NKT cell development reflects that these cells require the PDK1 substrate protein kinase B to meet the metabolic demands for proliferative expansion in response to IL-15 or AgR stimulation. There is also constitutive PDK1 signaling in conventional ?/? T cells that is not required for lineage commitment of these cells but fine-tunes the expression of coreceptors and adhesion molecules. Also, although PDK1 is dispensable for thymic development of conventional ?/? T cells, peripheral cells are reduced substantially. This reflects a PDK1 requirement for lymphopenia-induced proliferation, a process necessary for initial population of the peripheral T cell niche in neonatal mice. PDK1 is thus indispensable for T cell developmental programs, but the timing of the PDK1 requirement is unique to different T cell subpopulations. PMID:20944007

Finlay, David K; Kelly, April P; Clarke, Rosemary; Sinclair, Linda V; Deak, Maria; Alessi, Dario R; Cantrell, Doreen A

2010-11-15

220

Development of skewed functionality of HIV-1-specific cytotoxic CD8(+) T cells from primary to early chronic phase of HIV infection.  

PubMed

In recent years, the prevalence of HIV-1 infection has been rapidly increasing among men who have sex with men (MSM). However, it remains unknown how the host immune system responds to the infection in this population. We assessed the quantity of HIV-specific CD8(+) T-cell responses by using Elispot assay and their functionalities by measuring 5 CD8(+) T-cell evaluations (IL-2, MIP-1?, CD107a, TNF-?, IFN-?) with flow cytometry assays among 18 primarily and 37 early chronically HIV-infected MSM. Our results demonstrated that subjects at early chronic phase developed HIV-specific CD8(+) T-cell responses with higher magnitudes and more diversified functionalities in comparison with those at primary infection. However, populations with IL-2(+) CD107a(+) or in combination with other functionality failed to develop in parallel. The multifunctional but not monofunctional HIV-specific CD8(+) T cells were associated with higher CD4(+) T -cell counts and lower viral loads. These data revealed that prolonged infection from primary to early chronic infection could selectively increase the functionalities of HIV-specific CD8(+) T cells in HIV-infected MSM population, the failure to develop IL-2 and cytotoxic functionalities in parallel may explain why the increased HIV-specific CD8(+) T cells were unable to enhance the containment of HIV-1 replication at the early chronic stage. PMID:23028721

Wang, Wanhai; Qiu, Chenli; Qiu, Chao; Wang, Ying; Zhang, Xiaoyan; Xu, Jianqing

2012-01-01

221

A Self-Reactive TCR Drives the Development of Foxp3+ Regulatory T Cells that Prevent Autoimmune Disease1  

PubMed Central

Although Foxp3+ regulatory T (Treg) cells are thought to express autoreactive TCRs, it is not clear how individual TCRs influence Treg cell development, phenotype, and function in vivo. We have generated TCR transgenic mice (termed SFZ70 mice) using Tcra and Tcrb genes cloned from an autoreactive CD4+ T cell isolated from a Treg cell-deficient scurfy mouse. The SFZ70 TCR recognizes a cutaneous autoantigen and drives development of both conventional CD4+ Foxp3? T cells (Tconv) and Foxp3+ Treg cells. SFZ70 Treg cells display an activated phenotype evidenced by robust proliferation and expression of skin-homing molecules such as CD103 and P-selectin ligand. Analysis of Foxp3-deficient SFZ70 mice demonstrates Treg cells inhibit Tconv cell expression of tissue-homing receptors and their production of pro-inflammatory cytokines. Additionally, Treg cell suppression of SFZ70 Tconv cells can is overcome by non-specific activation of antigen-presenting cells. These results provide new insights into the differentiation and function of tissue-specific Treg cells in vivo and provide a tractable system for analyzing the molecular requirements of Treg cell-mediated tolerance toward a cutaneous autoantigen.

Killebrew, Justin R.; Perdue, Nikole; Kwan, Alan; Thornton, Angela M.; Shevach, Ethan M.; Campbell, Daniel J.

2011-01-01

222

T cell development from kit-negative progenitors in the Foxn1Delta/Delta mutant thymus.  

PubMed

Foxn1Delta is a hypomorphic allele of the nude gene that causes arrested thymic epithelial cell differentiation and abnormal thymic architecture lacking cortical and medullary domains. T cells develop in the Foxn1Delta/Delta adult thymus to the double- and single-positive stages, but in the apparent absence of double-negative 3 (DN3) cells; however, DN3 cells are present in the fetal thymus. To investigate the origin of this seemingly contradictory phenotype, we performed an analysis of fetal and adult DN cells in these mutants. Neither adult bone marrow-derived cells nor fetal liver cells from wild-type or Rag1-/- mice were able to differentiate to the DN2 or DN3 stage in the Foxn1Delta/Delta thymus. Our data suggest that thymopoiesis in the Foxn1Delta/Delta adult thymus proceeds from CD117- atypical progenitors, while CD117+ DN1a cells are absent or blocked in their ability to differentiate to the T lineage. Wild-type cells generated by this pathway in the postnatal thymus were exported to the periphery, demonstrating that these atypical cells contributed to the peripheral T cell pool. The Foxn1Delta/Delta adult (but not fetal) thymus also preferentially supports B cell development, specifically of the B-1 type, and this phenotype correlated with reduced Notch ligand expression in the adult stroma. PMID:18178831

Xiao, Shiyun; Su, Dong-ming; Manley, Nancy R

2008-01-15

223

G Protein-Coupled Receptor 83 Is Dispensable for the Development and Function of Regulatory T Cells?  

PubMed Central

Global analyses of gene expression in regulatory T (Treg) cells, whose development is critically dependent upon the transcription factor Foxp3, have provided many clues as to the molecular mechanisms these cells employ to control immune responses and establish immune tolerance. Through these studies, G protein-coupled receptor 83 (GPR83) was found to be expressed at high levels in Treg-cell populations. However, its function remained unclear. Recently, it has been suggested that GPR83 is involved in the induction of Foxp3 expression in the peripheral nonregulatory Foxp3? CD4 T cells. To examine a role for GPR83 in Treg-cell biology, we generated and characterized GPR83-deficient mice. We have shown that GPR83 abolition does not result in measurable pathology or changes in the numbers or function of Foxp3+ Treg cells. Furthermore, while in vitro analysis suggested a potential involvement of GPR83 in transforming growth factor ?-dependent Foxp3 induction, there was no difference in the ability of nonregulatory GPR83-deficient and nondeficient Foxp3? T cells to acquire Foxp3 expression in vivo. Collectively, our results demonstrate that GPR83 is dispensable for Treg-cell development and function.

Lu, Li-Fan; Gavin, Marc A.; Rasmussen, Jeffrey P.; Rudensky, Alexander Y.

2007-01-01

224

G protein-coupled receptor 83 is dispensable for the development and function of regulatory T cells.  

PubMed

Global analyses of gene expression in regulatory T (Treg) cells, whose development is critically dependent upon the transcription factor Foxp3, have provided many clues as to the molecular mechanisms these cells employ to control immune responses and establish immune tolerance. Through these studies, G protein-coupled receptor 83 (GPR83) was found to be expressed at high levels in Treg-cell populations. However, its function remained unclear. Recently, it has been suggested that GPR83 is involved in the induction of Foxp3 expression in the peripheral nonregulatory Foxp3- CD4 T cells. To examine a role for GPR83 in Treg-cell biology, we generated and characterized GPR83-deficient mice. We have shown that GPR83 abolition does not result in measurable pathology or changes in the numbers or function of Foxp3+ Treg cells. Furthermore, while in vitro analysis suggested a potential involvement of GPR83 in transforming growth factor beta-dependent Foxp3 induction, there was no difference in the ability of nonregulatory GPR83-deficient and nondeficient Foxp3- T cells to acquire Foxp3 expression in vivo. Collectively, our results demonstrate that GPR83 is dispensable for Treg-cell development and function. PMID:17893329

Lu, Li-Fan; Gavin, Marc A; Rasmussen, Jeffrey P; Rudensky, Alexander Y

2007-12-01

225

Notch Ligand Delta-Like 4 Blockade Alleviates Experimental Autoimmune Encephalomyelitis by Promoting Regulatory T Cell Development  

PubMed Central

Notch signaling pathway plays an important role in T cell differentiation. Delta-like ligand (Dll)4, one of five known Notch ligands, has been implicated in regulating Th2 cell differentiation in animal models of human diseases. However, the role of Dll4 in Th1/Th17-mediated autoimmune diseases remains largely unknown. Using an anti-Dll4 blocking mAb, we show that neutralizing Dll4 during the induction phase of experimental autoimmune encephalomyelitis in C57BL/6 mice significantly increased the pool of CD4+Foxp3+ regulatory T cells (Treg) in the periphery and in the CNS, and decreased the severity of clinical disease and CNS inflammation. Dll4 blockade promoted induction of myelin-specific Th2/Treg immune responses and impaired Th1/Th17 responses compared with IgG-treated mice. In vitro, we show that signaling with recombinant Dll4 inhibits the TGF-?–induced Treg development, and inhibits Janus kinase 3-induced STAT5 phosphorylation, a transcription factor known to play a key role in Foxp3 expression and maintenance. Depletion of natural Treg using anti-CD25 Ab reversed the protective effects of anti-Dll4 Ab. These findings outline a novel role for Dll4–Notch signaling in regulating Treg development in EAE, making it an encouraging target for Treg-mediated immunotherapy in autoimmune diseases, such as multiple sclerosis.

Bassil, Ribal; Zhu, Bing; Lahoud, Youmna; Riella, Leonardo V.; Yagita, Hideo; Elyaman, Wassim; Khoury, Samia J.

2012-01-01

226

Molecular Evidence for a Thymus-Independent Partial T Cell Development in a FOXN1?/? Athymic Human Fetus  

PubMed Central

The thymus is the primary organ able to support T cell ontogeny, abrogated in FOXN1?/? human athymia. Although evidence indicates that in animal models T lymphocytes may differentiate at extrathymic sites, whether this process is really thymus-independent has still to be clarified. In an athymic FOXN1?/? fetus, in which we previously described a total blockage of CD4+ and partial blockage of CD8+ cell development, we investigated whether intestine could play a role as extrathymic site of T-lymphopoiesis in humans. We document the presence of few extrathymically developed T lymphocytes and the presence in the intestine of CD3+ and CD8+, but not of CD4+ cells, a few of them exhibiting a CD45RA+ naïve phenotype. The expression of CD3??pT?, RAG1 and RAG2 transcripts in the intestine and TCR gene rearrangement was also documented, thus indicating that in humans the partial T cell ontogeny occurring at extrathymic sites is a thymus- and FOXN1-independent process.

Fusco, Anna; Panico, Luigi; Gorrese, Marisa; Bianchino, Gabriella; Barone, Maria V.; Grieco, Vitina; Vitiello, Laura; D'Assante, Roberta; Romano, Rosa; Palamaro, Loredana; Scalia, Giulia; Vecchio, Luigi Del; Pignata, Claudio

2013-01-01

227

Rhizoctonia Bataticola Lectin (RBL) Induces Caspase-8-Mediated Apoptosis in Human T-Cell Leukemia Cell Lines but Not in Normal CD3 and CD34 Positive Cells  

PubMed Central

We have previously demonstrated immunostimulatory activity of a fungal lectin, Rhizoctonia bataticola lectin (RBL), towards normal human peripheral blood mononuclear cells. The present study aimed to explore the anticancer activities of RBL using human leukemic T-cell lines, Molt-4, Jurkat and HuT-78. RBL exhibited significant binding (>90%) to the cell membrane that was effectively inhibited by complex glycoproteins such as mucin (97% inhibition) and asialofetuin (94% inhibition) but not simple sugars such as N-acetyl-D-galactosamine, glucose and sucrose. RBL induced a dose and time dependent inhibition of proliferation and induced cytotoxicity in the cell lines. The percentage of apoptotic cells, as determined by hypodiploidy, was 33% and 42% in Molt-4 and Jurkat cells, respectively, compared to 3.11% and 2.92% in controls. This effect was associated with a concomitant decrease in the G0/G1 population. Though initiator caspase-8 and -9 were activated upon exposure to RBL, inhibition of caspase-8 but not caspase-9 rescued cells from RBL-induced apoptosis. Mechanistic studies revealed that RBL induced cleavage of Bid, loss of mitochondrial membrane potential and activation of caspase-3. The expression of the anti-apoptotic proteins Bcl-2 and Bcl-X was down regulated without altering the expression of pro-apoptotic proteins- Bad and Bax. In contrast to leukemic cells, RBL did not induce apoptosis in normal PBMC, isolated CD3+ve cells and undifferentiated CD34+ve hematopoietic stem and progenitor cells (HSPCs). The findings highlight the differential effects of RBL on transformed and normal hematopoietic cells and suggest that RBL may be explored for therapeutic applications in leukemia.

Pujari, Radha; Eligar, Sachin M.; Kumar, Natesh; Barkeer, Srikanth; Reddy, Vishwanath; Swamy, Bale M.; Inamdar, Shashikala R.; Shastry, Padma

2013-01-01

228

Epitope-Specific CD8+ T Cells Play a Differential Pathogenic Role in the Development of a Viral Disease Model for Multiple Sclerosis  

PubMed Central

Theiler's virus-induced demyelinating disease has been extensively investigated as a model for persistent viral infection and multiple sclerosis (MS). However, the role of CD8+ T cells in the development of disease remains unclear. To assess the role of virus-specific CD8+ T cells in the pathogenesis of demyelinating disease, a single amino acid substitution was introduced into the predominant viral epitope (VP3 from residues 159 to 166 [VP3159-166]) and/or a subdominant viral epitope (VP3173-181) of susceptible SJL/J mice by site-directed mutagenesis. The resulting variant viruses (N160V, P179A, and N160V/P179A) failed to induce CD8+ T cell responses to the respective epitopes. Surprisingly, mice infected with N160V or N160V/P179A virus, which lacks CD8+ T cells against VP3159-166, did not develop demyelinating disease, in contrast to wild-type virus or P179A virus lacking VP3173-181-specific CD8+ T cells. Our findings clearly show that the presence of VP3159-166-specific CD8+ T cells, rather than viral persistence itself, is strongly correlated with disease development. VP3173-181-specific CD8+ T cells in the central nervous system (CNS) of these virus-infected mice expressed higher levels of transforming growth factor ?, forkhead box P3, interleukin-22 (IL-22), and IL-17 mRNA but caused minimal cytotoxicity compared to that caused by VP3159-166-specific CD8+ T cells. VP3159-166-specific CD8+ T cells exhibited high functional avidity for gamma interferon production, whereas VP3173-181-specific CD8+ T cells showed low avidity. To our knowledge, this is the first report indicating that the induction of the IL-17-producing CD8+ T cell type is largely epitope specific and that this specificity apparently plays a differential role in the pathogenicity of virus-induced demyelinating disease. These results strongly advocate for the careful consideration of CD8+ T cell-mediated intervention of virus-induced inflammatory diseases.

Myoung, Jinjong; Kang, Hyun Seok; Hou, Wanqiu; Meng, Liping; Dal Canto, Mauro C.

2012-01-01

229

Development of ?? T cell subset responses in gnotobiotic pigs infected with human rotaviruses and colonized with probiotic lactobacilli  

PubMed Central

?? T cell responses are induced by various viral and bacterial infections. Different ?? T cells contribute to activation and regulation of the inflammatory response and to epithelial repair. How ?? T cells respond to rotavirus infection and how the colonization of probiotics influences the ?? T cell response were unknown. In this study, we evaluated by multicolor flow cytometry the frequencies and distribution of total ?? T cells and three major subsets (CD2?CD8?, CD2+CD8? and CD2+CD8+) in ileum, spleen and blood of gnotobiotic (Gn) pigs at early (3–5 days) and late phases (28 days) after rotavirus infection. The Gn pigs were inoculated with the virulent human rotavirus Wa strain and colonized with a mixture of two strains of probiotics Lactobacillus acidophilus and Lactobacillus reuteri. In naive pigs, the highest frequency of total ?? T cells was found in blood, followed by spleen and ileum at the early age (8–10 days old) whereas in older pigs (32 days of age) the highest frequency of total ?? T cells was found in ileum and spleen followed by blood. Rotavirus infection significantly increased frequencies of intestinal total ?? T cells and the putatively regulatory CD2+CD8+ ?? T cell subset and decreased frequencies of the putatively proinflammatory CD8? subsets in ileum, spleen and blood at post-infection days (PID) 3 or 5. The three ?? T cell subsets distributed and responded differently after rotavirus infection and/or lactobacilli colonization. The CD2+CD8+ subset contributed the most to the expansion of total ?? T cells after rotavirus infection in ileum because more than 77% of the total ?? T cells there were CD2+CD8+ cells. There was an additive effect between lactobacilli and rotavirus in inducing total ?? T cell expansion in ileum at PID 5. The overall effect of lactobacilli colonization versus rotavirus infection on frequencies of the CD2+CD8+ ?? T cell subset in ileum was similar; however, rotavirus-infected pigs maintained significantly higher frequencies of CD8? subsets in ileum than lactobacilli-colonized pigs. The dynamic ?? T cell responses suggest that ?? T cell subsets may play important roles in different stages of immune responses after rotavirus infection and probiotic colonization. The knowledge on the kinetics and distribution patterns of ?? T cell subsets in naïve pigs and after rotavirus infection or lactobacilli colonization provides the foundation for further mechanistic studies of their functions.

Wen, Ke; Li, Guohua; Zhang, Wei; Azevedo, Marli SP; Saif, Linda J; Liu, Fangning; Bui, Tammy; Yousef, Ahmed; Yuan, Lijuan

2011-01-01

230

Processing of Tumor Antigen Differentially Impacts the Development of Helper and Effector CD4+ T-cell Responses  

PubMed Central

CD4+ T cells contribute to the antitumor T-cell response as both effectors that promote tumor rejection and helpers that facilitate the activation of other antitumor effector cells, such as CD8+ T cells. Maximal engagement of both effector and helper CD4+ T-cell responses is a desirable attribute of cancer vaccines. We have employed the B16F10 murine melanoma model and a series of recombinant adenovirus (Ad) vaccines expressing mutant forms of the tumor antigen, dopachrome tautomerase, to investigate the relationship between antigen processing and the antitumor CD4+ T-cell response. Our results have revealed an unexpected dichotomy in the generation of helper and effector CD4+ T-cell responses where CD4+ T effector responses are dependent upon protein processing and trafficking, whereas CD4+ T helper responses are not. The results have important implications for strategies aimed at augmenting antigen immunogenicity by altering intracellular processing and localization.

Bernard, Dannie; Ventresca, Michael S; Marshall, Laura A; Evelegh, Carole; Wan, Yonghong; Bramson, Jonathan L

2010-01-01

231

Regulation of pre-T cell receptor (pT alpha-TCR beta) gene expression during human thymic development  

PubMed Central

In murine T cell development, early thymocytes that productively rearrange the T cell receptor (TCR) beta locus are selected to continue maturation, before TCR alpha expression, by means of a pre-TCR alpha- (pT alpha-) TCR beta heterodimer (pre-TCR). The aim of this study was to identify equivalent stages in human thymocyte development. We show here that variable-diversity-joining region TCR beta rearrangement and the expression of full-length TCR beta transcripts have been initiated in some immature thymocytes at the TCR alpha/beta- CD4+CD8- stage, and become common in a downstream subset of TCR alpha/beta- CD4+CD8+ thymocytes that is highly enriched in large cycling cells. TCR beta chain expression was hardly detected in TCR alpha/beta- CD4+CD8- thymocytes, whereas cytoplasmic TCR beta chain was found in virtually all TCR alpha/beta- CD4+CD8+ blasts. In addition, a TCR beta complex distinct from the mature TCR alpha/beta heterodimer was immunoprecipitated only from the latter subset. cDNA derived from TCR alpha/beta- CD4+CD8+ blasts allowed us to identify and clone the gene encoding the human pT alpha chain, and to examine its expression at different stages of thymocyte development. Our results show that high pT alpha transcription occurs only in CD4+CD8- and CD4+CD8+ TCR alpha/beta- thymocytes, whereas it is weaker in earlier and later stages of development. Based on these results, we propose that the transition from TCR alpha/beta- CD4+CD8- to TCR alpha/beta- CD4+CD8+ thymocytes represents a critical developmental stage at which the successful expression of TCR beta promotes the clonal expansion and further maturation of human thymocytes, independent of TCR alpha.

1996-01-01

232

Lymphoid tissue inducer cells maintain memory CD4 T cells within secondary lymphoid tissue  

PubMed Central

Phylogeny shows that CD4 T cell memory and lymph nodes (LNs) co-evolved in placental mammals. In ontogeny, retinoic acid orphan receptor (ROR) ?-dependent lymphoid tissue inducer (LTi) cells program the development of mammalian LNs. Here, we show that while primary CD4 T cell expansion is normal in ROR?-deficient mice, the persistence of memory CD4 T cells is ROR?-dependent. Furthermore, using bone marrow chimeric mice we demonstrate that LTi cells are the key ROR?-expressing cell type sufficient for memory CD4 T cell survival in the absence of persistent antigen. This effect was specific for CD4 T cells, since memory CD8 T cells survived equally well in the presence or absence of LTi cells. These data demonstrate a novel role for LTi cells, archetypal members of the innate lymphoid cell family, in supporting memory CD4 T cell survival in vivo.

Withers, David R.; Gaspal, Fabrina M.; Mackley, Emma C.; Marriott, Clare L.; Ross, Ewan A.; Desanti, Guillaume E.; Roberts, Natalie A.; White, Andrea J.; Flores-Langarica, Adriana; McConnell, Fiona M.; Anderson, Graham; Lane, Peter J.L.

2012-01-01

233

Stable T cell-dendritic cell interactions precede the development of both tolerance and immunity in vivo  

PubMed Central

The maturation status of dendritic cells (DCs) determines whether they prime or tolerize T cells. We targeted ovalbumin peptide exclusively to DCs in situ using an antibody against DEC-205 and studied DC interaction with naïve CD4+ T cells under tolerizing or priming conditions. Two-photon microscopy was used to simultaneously track antigen-specific OT-II T cells, non-specific T cells and DCs in lymph nodes of living mice. In both tolerance and immunity, OT-II cells arrested on DCs near high endothelial venules beginning shortly after extravasation and regained their baseline speed by 18 h. Thus, early antigen-dependent T cell arrest on DCs is a shared feature of tolerance and priming associated with activation and proliferation.

Shakhar, Guy; Lindquist, Randall L.; Skokos, Dimitris; Dudziak, Diana; Huang, Julie H.; Nussenzweig, Michel C.; Dustin, Michael L.

2005-01-01

234

Dendritic cells drive memory CD8 T-cell homeostasis via IL-15 transpresentation  

PubMed Central

Interleukin-15 (IL-15) is crucial for the development of naive and memory CD8 T cells and is delivered through a mechanism called transpresentation. Previous studies showed that memory CD8 T cells require IL-15 transpresentation by an as yet unknown cell of hematopoietic origin. We hypothesized that dendritic cells (DCs) transpresent IL-15 to CD8 T cells, and we examined this by developing a transgenic model that limits IL-15 transpresentation to DCs. In this study, IL-15 transpresentation by DCs had little effect on restoring naive CD8 T cells but contributed to the development of memory-phenotype CD8 T cells. The generation of virus-specific, memory CD8 T cells was partially supported by IL-15R?+ DCs through the preferential enhancement of a subset of KLRG-1+CD27? CD8 T cells. In contrast, these DCs were largely sufficient in driving normal homeostatic proliferation of established memory CD8 T cells, suggesting that memory CD8 T cells grow more dependent on IL-15 transpresentation by DCs. Overall, our study clearly supports a role for DCs in memory CD8 T-cell homeostasis but also provides evidence that other hematopoietic cells are involved in this function. The identification of DCs fulfilling this role will enable future studies to better focus on mechanisms regulating T-cell homeostasis.

Stonier, Spencer W.; Ma, Lisa J.; Castillo, Eliseo F.

2008-01-01

235

Characterizing T-Cell Autoimmunity  

Microsoft Academic Search

\\u000a Immunological mechanisms which precipitate autoimmune diabetes involve the influence of a genetic footprint on the phenotype\\u000a of the T-cell response to self-antigens, and on development of pathological outcomes in immune responses resulting in T1D.\\u000a For one of the human diabetes antigens, proinsulin, recent findings allow the emergence of a model in which elements of genetically\\u000a biased T-cell development and peptide

Ivana Durinovic-Belló; Gerald T. Nepom

236

Role of recycling, Mindbomb1 association, and exclusion from lipid rafts of ?-like 4 for effective Notch signaling to drive T cell development.  

PubMed

Intrathymic T cell development is predicated on the Notch1 ligand Delta-like (Dll) 4. However, both Dll4 and Dll1 can support T cell development in vitro. Endocytosis of Dll1 is important for Notch activation, whereas currently there is no evidence for the role of Dll4 endocytosis in T cell development. To elucidate this, we generated Dll4 constructs that modify or inhibit endocytosis. Our results show that targeting the intracellular domain affects Dll4's ability to induce Notch target gene expression, support efficient T cell development, and inhibit B cell development. Dll4 function relies on a combination of factors, which include strong Mindbomb1 (Mib1) association, ubiquitination, and internalization and recycling back to the cell surface, to engage Notch1 effectively. Distinct membrane localization and the Delta/Serrate/Lag2 (DSL) domain were important for Dll4 function. These features are consistent with a "recycling" model, but not in opposition to a "mechano-transduction" model, whereby Dll4 is able to engage Notch and create a pulling force required to activate signaling, leading to the induction of T-lineage development. Taken together, in contrast to Dll1, Dll4 does not localize to lipid rafts and shows stronger association with Mib1 and increased Notch1 uptake, which likely account for its superior ability to induce T cell development. PMID:23162128

Shah, Divya K; Mohtashami, Mahmood; Zúñiga-Pflücker, Juan Carlos

2012-12-15

237

A Novel Molecular Complex Expressed on Immature B Cells: A Possible Role in T Cell-Independent B Cell Development  

PubMed Central

To identify surface molecules that may play a role in regulating ileal Peyer's patch (PP) B cell growth, we generated monoclonal antibodies (mAbs) and then selected them for a unique reactivity with ileal PP B cells. Flow cytometric analysis identified a mAb (SIC4.8R) that labeled 97% of ileal and 50–60% of jejunal PP sIgM+B cells. SIC4.8R also labeled a subpopulation of cortical thymocytes but few B or T cells in other lymphoid tissues, including bone marrow. Immunohistochemistry revealed intense SIC4.8R staining of B cells in the cortex of ileal PP follicles. SIC4.8R also labeled bovine PP B cells, a murine pro-B cell line, and pre-B cells in human bone marrow. Protein chemistry revealed that a structurally similar molecular complex was expressed on sheep ileal PP B cells and thymocytes and murine pro-B cells. Addition of soluble SIC4.8R to cultured ileal PP B cells reduced apoptotic cell death, elevated proliferative responses, partially inhibited anti-Ig-induced cell death, and induced IL-4 responsiveness. In contrast, soluble SIC4.8R had an antiproliferative effect on a mouse pro-B cell line. Finally, SIC4.8R labeling declined following the stimulation of ileal PP B cells with CD40 ligand. In conclusion, the present investigation determined that SIC4.8R identified a novel molecular complex that is expressed at several stages of T cell-independent B cell development in a variety of mammalian species. This observation confirmed that PP B cells are developmentally distinct from other B cell populations in sheep and suggested that the bone marrow may not be a site of B lymphopoiesis in young lambs.

Ghia, Paolo; Grawunder, Ulf; Ferrari, Giorgio

1996-01-01

238

A novel molecular complex expressed on immature B cells: a possible role in T cell-independent B cell development.  

PubMed

To identify surface molecules that may play a role in regulating ileal Peyer's patch (PP) B cell growth, we generated monoclonal antibodies (mAbs) and then selected them for a unique reactivity with ileal PP B cells. Flow cytometric analysis identified a mAb (SIC4.8R) that labeled 97% of ileal and 50-60% of jejunal PP sIgM+B cells. SIC4.8R also labeled a subpopulation of cortical thymocytes buy few B or T cells in other lymphoid tissues, including bone marrow. Immunohistochemistry revealed intense SIC4.8R staining of B cells in the cortex of ileal PP follicles. SIC4.8R also labeled bovine PP B cells, a murine pro-B cell line, and pre-B cells in human bone marrow. Protein chemistry revealed that a structurally similar molecular complex was expressed on sheep ileal PP B cells and thymocytes and murine pro-B cells. Addition of soluble SIC4.8R to cultured ileal PP B cells reduced apoptotic cell death, elevated proliferative responses, partially inhibited anti-Ig-induced cell death, and induced IL-4 responsiveness. In contrast, soluble SIC4.8R had an antiproliferative effect on a mouse pro-B cell line. Finally, SIC4.8R labeling declined following the stimulation of ileal PP B cells with CD40 ligand. In conclusion, the present investigation determined that SIC4.8R identified a novel molecular complex that is expressed at several stages of T cell-independent B cell development in a variety of mammalian species. This observation confirmed that PP B cells are developmentally distinct from other B cell populations in sheep and suggested that the bone marrow may not be a site of B lymphopoiesis in young lambs. PMID:8828012

Griebel, P J; Ghia, P; Grawunder, U; Ferrari, G

1996-01-01

239

3-Hydroxykynurenine Suppresses CD4+ T-Cell Proliferation, Induces T-Regulatory-Cell Development, and Prolongs Corneal Allograft Survival  

PubMed Central

Purpose. IDO (indoleamine 2,3-dioxygenase) modulates the immune response by depletion of the essential amino acid tryptophan, and IDO overexpression has been shown to prolong corneal allograft survival. This study was conducted to examine the effect of kynurenines, the products of tryptophan breakdown and known to act directly on T lymphocytes, on corneal graft survival. Methods. The effects of kynurenines on T-cell proliferation and death, T-regulatory-cell development, and dendritic cell function, phenotype, and viability were analyzed in vitro. The effect of topical and systemic administration of 3-hydroxykynurenine (3HK) on orthotopic murine corneal allograft survival was examined. Results. T-lymphocyte proliferation was inhibited by two of the four different kynurenines: 3HK and 3-hydroxyanthranilic acid (3HAA). This effect was accompanied by significant T-cell death. Neither 3HK nor 3HAA altered dendritic cell function, nor did they induce apoptosis or pathogenicity to corneal endothelial cells. Administration of systemic and topical 3HK to mice receiving a fully mismatched corneal graft resulted in significant prolongation of graft survival (median survival of control grafts, 12 days; of treated, 19 and 15 days, respectively; P < 0.0003). While systemic administration of 3HK was associated with a significant depletion of CD4+ T, CD8+ T, and B lymphocytes in peripheral blood, no depletion was found after topical administration. Conclusions. The production of kynurenines, in particular 3HK and 3HAA, may be one mechanism (in addition to tryptophan depletion) by which IDO prolongs graft survival. These molecules have potential as specific agents for preventing allograft rejection in patients at high rejection risk.

Zaher, Sarah S.; Germain, Conrad; Fu, Hongmei; Larkin, Daniel F. P.

2011-01-01

240

Developing T-Cell Therapies for Cancer in an Academic Setting  

Microsoft Academic Search

The development of targeted drug therapies for cancer has been a long-term ambition of clinicians and researchers alike. While\\u000a most effort has been expended on identifying small molecule therapeutics, the immune system can be manipulated to provide\\u000a biological components that will be the most targeted of all. Exploitation of the humoral immune system by manufacture of monoclonal\\u000a antibodies has already

Malcolm K. Brenner

241

Regulation of DC development and DC-mediated T-cell immunity via CISH  

PubMed Central

Cytokine inducible SH2-containing protein (CISH) plays a crucial role in type 1 dendritic cell (DC) development as well as in the DC-mediated activation of cytotoxic T lymphocytes (CTLs). CISH expression at late DC developmental stages shuts down the proliferation of DC progenitors by negatively regulating signal transducer and activator of transcription 5 (STAT5) and facilitates the differentiation of DCs into potent stimulators of CTLs.

Miah, Mohammad Alam; Bae, Yong-Soo

2013-01-01

242

Dynamic regulation of notch 1 and notch 2 surface expression during T cell development and activation revealed by novel monoclonal antibodies.  

PubMed

It is well established that Notch signaling plays a critical role at multiple stages of T cell development and activation. However, detailed analysis of the cellular and molecular events associated with Notch signaling in T cells is hampered by the lack of reagents that can unambiguously measure cell surface Notch receptor expression. Using novel rat mAbs directed against the extracellular domains of Notch1 and Notch2, we find that Notch1 is already highly expressed on common lymphoid precursors in the bone marrow and remains at high levels during intrathymic maturation of CD4(-)CD8(-) thymocytes. Notch1 is progressively down-regulated at the CD4(+)CD8(+) and mature CD4(+) or CD8(+) thymic stages and is expressed at low levels on peripheral T cells. Immunofluorescence staining of thymus cryosections further revealed a localization of Notch1(+)CD25(-) cells adjacent to the thymus capsule. Notch1 was up-regulated on peripheral T cells following activation in vitro with anti-CD3 mAbs or infection in vivo with lymphocytic chorio-meningitis virus or Leishmania major. In contrast to Notch1, Notch2 was expressed at intermediate levels on common lymphoid precursors and CD117(+) early intrathymic subsets, but disappeared completely at subsequent stages of T cell development. However, transient up-regulation of Notch2 was also observed on peripheral T cells following anti-CD3 stimulation. Collectively our novel mAbs reveal a dynamic regulation of Notch1 and Notch2 surface expression during T cell development and activation. Furthermore they provide an important resource for future analysis of Notch receptors in various tissues including the hematopoietic system. PMID:19915064

Fiorini, Emma; Merck, Estelle; Wilson, Anne; Ferrero, Isabel; Jiang, Wei; Koch, Ute; Auderset, Floriane; Laurenti, Elisa; Tacchini-Cottier, Fabienne; Pierres, Michel; Radtke, Freddy; Luther, Sanjiv A; Macdonald, H Robson

2009-12-01

243

Regulatory T cells in rheumatoid arthritis  

Microsoft Academic Search

Apart from the deletion of autoreactive T cells in the thymus, various methods exist in the peripheral immune system to control\\u000a specific human immune responses to self-antigens. One of these mechanisms involves regulatory T cells, of which CD4+CD25+ T cells are a major subset. Recent evidence suggests that CD4+CD25+ T cells have a role in controlling the development of autoimmune

Jan Leipe; Alla Skapenko; Peter E Lipsky; Hendrik Schulze-Koops

2005-01-01

244

T cell repertoires and competitive exclusion  

Microsoft Academic Search

Self-renewal is generally thought to play a major role in the maintenance of the T-cell repertoire. Here we develop a set of mathematical models for T-cell activation by peptides on antigen presenting cells (APCs). We show that competition between T cells is inherent to the processes involved in T cells binding APCs. We prove that for each dominant peptide only

R. J. de Boer; A. S. Perelson

1994-01-01

245

Antihelper T cell autoantibody in acquired agammaglobulinemia.  

PubMed Central

A patient with acquired agammaglobulinemia had an antihelper T cell factor that was identified as an immunoglobulin of the IgG class. The factor specifically bound to the TH2- T cell subset and, in the presence of complement, abolished the helper effect of normal T cells. The antihelper T cell antibody preceded by several years the appearance of suppressor TH2+Ia+ T cells, at which time the clinical course rapidly deteriorated. Plasmapheresis resulted in lymphocytosis and reappearance of a functionally intact helper T cell population. It did not affect the suppressor cells. Conversely, total thymectomy resulted in a temporary disappearance of the TH2+Ia+ suppressor cells, but did not decrease the levels of the autoantibody to helper T cells. Neither of these treatments reversed the state of agammaglobulinemia.

Rubinstein, A; Sicklick, M; Mehra, V; Rosen, F S; Levey, R H

1981-01-01

246

Thymic output, T-cell diversity, and T-cell function in long-term human SCID chimeras  

PubMed Central

Severe combined immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T, B, and sometimes NK-cell function. Nonablative human leukocyte antigen–identical or rigorously T cell–depleted haploidentical parental bone marrow transplantation (BMT) results in thymus-dependent genetically donor T-cell development in the recipients, leading to long-term survival. We reported previously that normal T-cell numbers, function, and repertoire developed by 3 to 4 months after transplantation in SCID patients, and the repertoire remained highly diverse for the first 10 years after BMT. The T-cell receptor diversity positively correlated with T-cell receptor excision circle levels, a reflection of thymic output. However, the fate of thymic function in SCID patients beyond 10 to 12 years after BMT remained to be determined. In this greater than 25-year follow-up study of 128 patients with 11 different molecular types of SCID after nonconditioned BMT, we provide evidence that T-cell function, thymic output, and T-cell clonal diversity are maintained long-term.

Win, Chan M.; Parrott, Roberta E.; Cooney, Myriah; Moser, Barry K.; Roberts, Joseph L.; Sempowski, Gregory D.; Buckley, Rebecca H.

2009-01-01

247

Thymic regulatory T cells.  

PubMed

Several types of T regulatory (Treg) cells have been described in both mice and humans, including natural or professional (CD4+CD25+ T cells) and adaptive (Th3 and Tr1 cells) Treg cells. The former develops in the thymus and results in an endogeneous long-lived population of self-antigen-specific T cells in the periphery poised to prevent potentially autoimmune reactions. The second subset develops as a consequence of activation of mature T cells under particular conditions of sub-optimal antigen exposure and/or costimulation. Natural Treg cells are positively selected in the cortex through their TCR interactions with self-peptides presented by thymic stromal cells. It is likely that this high-affinity recognition results in signals rendering them anergic and able to produce anti-apoptoptic molecules which protect them from negative selection. Recently, small subsets of CD4+CD25+ and of CD8+CD25+ cells sharing similar characteristics have been detected in human fetal and post-natal thymuses. Both CD4+CD25+ and CD8+CD25+ human thymocytes express Foxp3 and GITR mRNA, as well as surface CCR8 and TNFR2 and cytoplasmic CTLA-4 proteins, which are common features of mature Treg cells. Following activation they do not proliferate or produce cytokines, but express surface CTLA-4 and TGF-beta1. They suppress the proliferation of autologous CD4+CD25- thymocytes to allogeneic stimulation by a contact-dependent mechanism related to the combined action of surface CTLA-4 and TGF-beta leading to the inhibition of the IL-2R alpha chain on target T cells. Lastly, both CD4+CD25+ and CD8+CD25+ Treg thymocytes exert strong suppressive activity on Th1, but much lower on Th2 cells, since these latter may escape from suppression via their ability to respond to growth factors other than IL-2. Treg cells that develop in, and emerge from, the thymus are certainly responsible for the maintenance of self-tolerance and prevention of autoimmune disorders. The result that Th1 cells are highly susceptible to the suppressive activity of Treg thymocytes is consistent with the important role of these cells in protecting against the Th1-mediated immune response to autoantigens. PMID:16214099

Maggi, Enrico; Cosmi, Lorenzo; Liotta, Francesco; Romagnani, Paola; Romagnani, Sergio; Annunziato, Francesco

2005-11-01

248

Interaction of mature CD3+CD4+ T cells with dendritic cells triggers the development of tertiary lymphoid structures in the thyroid  

PubMed Central

Ectopic expression of CC chemokine ligand 21 (CCL21) in the thyroid leads to development of lymphoid structures that resemble those observed in Hashimoto thyroiditis. Deletion of the inhibitor of differentiation 2 (Id2) gene, essential for generation of CD3–CD4+ lymphoid tissue–inducer (LTi) cells and development of secondary lymphoid organs, did not affect formation of tertiary lymphoid structures. Rather, mature CD3+CD4+ T cells were critical for the development of tertiary lymphoid structures. The initial stages of this process involved interaction of CD3+CD4+ T cells with DCs, the appearance of peripheral-node addressin–positive (PNAd+) vessels, and production of chemokines that recruit lymphocytes and DCs. These findings indicate that the formation of tertiary lymphoid structures does not require Id2-dependent conventional LTis but depends on a program initiated by mature CD3+CD4+ T cells.

Marinkovic, Tatjana; Garin, Alexandre; Yokota, Yoshifumi; Fu, Yang-Xin; Ruddle, Nancy H.; Furtado, Glaucia C.; Lira, Sergio A.

2006-01-01

249

FoxP3 and Bcl-xL cooperatively promote regulatory T cell persistence and prevention of arthritis development  

Microsoft Academic Search

INTRODUCTION: Forkhead box p3 (FoxP3)-expressing regulatory T cells (Tregs) have been clearly implicated in the control of autoimmune disease in murine models. In addition, ectopic expression of FoxP3 conveys a Treg phenotype to CD4+ T cells, lending itself to therapeutic use in the prevention of rheumatoid arthritis (RA). In this study, we generated therapeutically active Tregs with an increased life

Rizwanul Haque; Fengyang Lei; Xiaofang Xiong; Yuzhang Wu; Jianxun Song

2010-01-01

250

Alteration of the Thymic T Cell Repertoire by Rotavirus Infection Is Associated with Delayed Type 1 Diabetes Development in Non-Obese Diabetic Mice  

PubMed Central

Rotaviruses are implicated as a viral trigger for the acceleration of type 1 diabetes in children. Infection of adult non-obese diabetic (NOD) mice with rotavirus strain RRV accelerates diabetes development, whereas RRV infection in infant NOD mice delays diabetes onset. In this study of infant mice, RRV titers and lymphocyte populations in the intestine, mesenteric lymph nodes (MLN) and thymus of NOD mice were compared with those in diabetes-resistant BALB/c and C57BL/6 mice. Enhanced intestinal RRV infection occurred in NOD mice compared with the other mouse strains. This was associated with increases in the frequency of CD8?? TCR?? intraepithelial lymphocytes, and their PD-L1 expression. Virus spread to the MLN and T cell numbers there also were greatest in NOD mice. Thymic RRV infection is shown here in all mouse strains, often in combination with alterations in T cell ontogeny. Infection lowered thymocyte numbers in infant NOD and C57BL/6 mice, whereas thymocyte production was unaltered overall in infant BALB/c mice. In the NOD mouse thymus, effector CD4+ T cell numbers were reduced by infection, whereas regulatory T cell numbers were maintained. It is proposed that maintenance of thymic regulatory T cell numbers may contribute to the increased suppression of inflammatory T cells in response to a strong stimulus observed in pancreatic lymph nodes of adult mice infected as infants. These findings show that rotavirus replication is enhanced in diabetes-prone mice, and provide evidence that thymic T cell alterations may contribute to the delayed diabetes onset following RRV infection.

Webster, Nicole L.; Zufferey, Christel; Pane, Jessica A.; Coulson, Barbara S.

2013-01-01

251

Developing an HIV cytotoxic T-lymphocyte vaccine: issues of CD8 T-cell quantity, quality and location.  

PubMed

Issues of quantity, quality and location impact the ability of CD8 T cells to mediate protection from infection. These issues are considered in light of human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) vaccination. Methods are reviewed that result in 100- to 1000-fold higher frequencies of vaccine-specific memory CD8 T cells than that achieved by current HIV/SIV vaccine approaches. Data demonstrating that location within mucosal tissues has a direct impact on memory CD8 T-cell function are discussed. Arguments are made that establishing memory CD8 T cells within mucosal sites of transmission, a priori to natural infection, may be essential for conferring optimal and rapid protection. Lastly, it is proposed that heterologous prime-boost vaccination with recombinant live replicating vectors, which has the potential to induce tremendous numbers of cytolytic memory CD8 T cells within mucosal tissues, would provide a far more stringent test of the hypothesis that memory CD8 T cells could, in principal, form the basis for a preventative HIV vaccine. PMID:19093965

Masopust, D

2009-01-01

252

Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors.  

PubMed

Most B-cell malignancies express CD19, and a majority of patients with B-cell malignancies are not cured by current standard therapies. Chimeric antigen receptors (CARs) are fusion proteins consisting of antigen recognition moieties and T-cell activation domains. T cells can be genetically modified to express CARs, and adoptive transfer of anti-CD19 CAR T cells is now being tested in clinical trials. Effective clinical treatment with anti-CD19 CAR T cells was first reported in 2010 after a patient with advanced-stage lymphoma treated at the NCI experienced a partial remission of lymphoma and long-term eradication of normal B cells. Additional patients have subsequently obtained long-term remissions of advanced-stage B-cell malignancies after infusions of anti-CD19 CAR T cells. Long-term eradication of normal CD19(+) B cells from patients receiving infusions of anti-CD19 CAR T cells demonstrates the potent antigen-specific activity of these T cells. Some patients treated with anti-CD19 CAR T cells have experienced acute adverse effects, which were associated with increased levels of serum inflammatory cytokines. Although anti-CD19 CAR T cells are at an early stage of development, the potent antigen-specific activity observed in patients suggests that infusions of anti-CD19 CAR T cells might become a standard therapy for some B-cell malignancies. PMID:23546520

Kochenderfer, James N; Rosenberg, Steven A

2013-05-01

253

Immunomodulatory role of the hepatocyte during HCV infection: driving CD4+CD25+Foxp3+ Regulatory T cell Development through the Tim-3/Gal-9 Pathway  

PubMed Central

Hepatitis C virus (HCV) is remarkable at disrupting human immunity to establish chronic infection. Accumulation of regulatory T cells (Tregs) and up-regulation of inhibitory signaling pathways (such as Tim-3/Gal-9) play pivotal roles in suppressing antiviral effector T cells (Teffs) that are essential for viral clearance. While Tim-3/Gal-9 interactions have been shown to negatively regulate Teffs, their role in regulating Tregs is poorly understood. To explore how Tim-3/Gal-9 interactions regulate HCV-mediated Treg development, in this study we provide pilot data showing that HCV-infected hepatocytes express higher levels of Gal-9 and TGF-?, and up-regulate Tim-3 expression and regulatory cytokines TGF-?/IL-10 in co-cultured CD4+ T cells, driving conventional CD4+ T cells into CD25+Foxp3+ Tregs. Additionally, recombinant Gal-9 protein can transform TCR-activated CD4+ T cells into Foxp3+ Tregs in a dose-dependent manner. Importantly, blocking Tim-3/Gal-9 ligations abrogates HCV-mediated Treg induction by HCV-infected hepatocytes, suggesting that Tim-3/Gal-9 interactions may regulate Foxp3+ Treg development and function during HCV infection.

Ji, Xiao J.; Ma, Cheng J.; Wang, Jia M.; Wu, Xiao Y.; Niki, Toshiro; Hirashima, Mitsumi; Moorman, Jonathan P.; Yao, Zhi Q.

2013-01-01

254

9-cis-retinoic acid inhibits activation-driven T-cell apoptosis: implications for retinoid X receptor involvement in thymocyte development.  

PubMed Central

Retinoic acid is a morphogenetic signaling molecule derived from vitamin A and involved in vertebrate development. Two groups of receptors, retinoic acid receptors and retinoid X receptors (RXRs), have been identified. All-trans-retinoic acid is the high-affinity ligand for retinoic acid receptors, and 9-cis-retinoic acid additionally binds RXRs with high affinity. Here we report that although retinoic acid has little inhibitory effect on activation-induced T-cell proliferation, it specifically prevents activation-induced apoptosis of T-cell hybridomas and antigen-specific deletion of immature CD4+CD8+ thymocytes from alpha beta T-cell receptor transgenic mice. 9-cis-Retinoic acid was approximately 10-fold more potent than all-trans-retinoic acid, suggesting that RXRs participate in this process. Thus, although 9-cis-retinoic acid has little immuno-suppressive activity, it is a potent negative regulator of activation-induced T-cell apoptosis, raising the possibility that RXRs may take part in regulating T-cell development.

Yang, Y; Vacchio, M S; Ashwell, J D

1993-01-01

255

Dual T cell receptor alpha chain T cells in autoimmunity  

PubMed Central

Allelic exclusion at the T cell receptor alpha locus TCR-alpha is incomplete, as demonstrated by the presence of a number of T lymphocyte clones carrying two expressed alpha chain products. Such dual alpha chain T cells have been proposed to play a role in autoimmunity, for example, because of a second TCR-alpha beta pair having bypassed negative selection by virtue of low expression. We examined this hypothesis by generating mice of various autoimmunity-prone strains carrying a hemizygous targeted disruption of the TCR-alpha locus, therefore unable to produce dual alpha chain T cells. Normal mice have a low but significant proportion of T cells expressing two cell-surface TCR-alpha chains that could be enumerated by comparison to TCR-alpha hemizygotes, which have none. Susceptibility to various autoimmune diseases was analyzed in TCR-alpha hemizygotes that had been backcrossed to disease-prone strains for several generations. The incidence of experimental allergic encephalomyelitis and of lupus is not affected by the absence of dual TCR-alpha cells. In contrast, nonobese diabetic (NOD) TCR alpha hemizygotes are significantly protected from cyclophosphamide-accelerated insulitis and diabetes. Thus, dual alpha T cells may play an important role in some but not all autoimmune diseases. Furthermore, since protected and susceptible NOD mice both show strong spontaneous responses to glutamic acid decarboxylase, responses to this antigen, if necessary for diabetetogenesis, are not sufficient.

1995-01-01

256

IL-3 attenuates collagen-induced arthritis by modulating the development of Foxp3+ regulatory T cells.  

PubMed

IL-3, a cytokine secreted by Th cells, functions as a link between the immune and the hematopoietic system. We previously demonstrated the potent inhibitory role of IL-3 on osteoclastogenesis, pathological bone resorption, and inflammatory arthritis. In this study, we investigated the novel role of IL-3 in development of regulatory T (Treg) cells. We found that IL-3 in a dose-dependent manner increases the percentage of Foxp3(+) Treg cells indirectly through secretion of IL-2 by non-Treg cells. These IL-3-expanded Treg cells are competent in suppressing effector T cell proliferation. Interestingly, IL-3 treatment significantly reduces the severity of arthritis and restores the loss of Foxp3(+) Treg cells in thymus, lymph nodes, and spleen in collagen-induced arthritis mice. Most significantly, we show that IL-3 decreases the production of proinflammatory cytokines IL-6, IL-17A, TNF-?, and IL-1 and increases the production of anti-inflammatory cytokines IFN-? and IL-10 in collagen-induced arthritis mice. Thus, to our knowledge, we provide the first evidence that IL-3 play an important role in modulation of Treg cell development in both in vitro and in vivo conditions, and we suggest its therapeutic potential in the treatment of rheumatoid arthritis and other autoimmune diseases. PMID:21242512

Srivastava, Rupesh K; Tomar, Geetanjali B; Barhanpurkar, Amruta P; Gupta, Navita; Pote, Satish T; Mishra, Gyan C; Wani, Mohan R

2011-02-15

257

Milk: an exosomal microRNA transmitter promoting thymic regulatory T cell maturation preventing the development of atopy?  

PubMed Central

Epidemiological evidence confirmed that raw cow’s milk consumption in the first year of life protects against the development of atopic diseases and increases the number of regulatory T-cells (Tregs). However, milk’s atopy-protective mode of action remains elusive. This review supported by translational research proposes that milk-derived microRNAs (miRs) may represent the missing candidates that promote long-term lineage commitment of Tregs downregulating IL-4/Th2-mediated atopic sensitization and effector immune responses. Milk transfers exosomal miRs including the ancient miR-155, which is important for the development of the immune system and controls pivotal target genes involved in the regulation of FoxP3 expression, IL-4 signaling, immunoglobulin class switching to IgE and Fc?RI expression. Boiling of milk abolishes milk’s exosomal miR-mediated bioactivity. Infant formula in comparison to human breast- or cow’s milk is deficient in bioactive exosomal miRs that may impair FoxP3 expression. The boost of milk-mediated miR may induce pivotal immunoregulatory and epigenetic modifications required for long-term thymic Treg lineage commitment explaining the atopy-protective effect of raw cow’s milk consumption. The presented concept offers a new option for the prevention of atopic diseases by the addition of physiological amounts of miR-155-enriched exosomes to infant formula for mothers incapable of breastfeeding.

2014-01-01

258

Modulation of T cell development and activation by novel members of the Schlafen (slfn) gene family harbouring an RNA helicase-like motif  

Microsoft Academic Search

The regulatory networks governing development and differentiation of hematopoietic cells are incompletely understood. Members of the Schlafen (Slfn) protein family have been implicated in the regulation of cell growth and T cell development. We have identified and chromosomally mapped four new members, slfn5, slfn8, slfn9 and slfn10, which belong to a distinct subgroup within this gene family. The characteristic feature

Peter Geserick; Frank Kaiser; Uwe Klemm; Stefan H. E. Kaufmann; Jens Zerrahn

2004-01-01

259

Down-regulation of normal human T cell blast activation: roles of APO2L/TRAIL, FasL, and c- FLIP, Bim, or Bcl-x isoform expression.  

PubMed

A systematic study was undertaken to characterize the role of APO 2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (APO2L/TRAIL) and Fas ligand (FasL) together with the expression of several anti- or proapoptotic proteins in the down-regulation of normal human T cell responses. We have observed for the first time that the higher sensitivity of normal human T cell blasts to apoptosis and activation-induced cell death (AICD) as compared with naive T cells correlates with the increased expression of Bcl-x short (Bcl-xS) and Bim. T cell blasts die in the absence of interleukin 2 (IL-2) with no additional effect of death receptor ligation. In the presence of IL-2, recombinant APO2L/TRAIL or cytotoxic anti-Fas monoclonal antibodies induce rather inhibition of IL-2-dependent growth and not cell death on normal human T cell blasts. This observation is of physiological relevance, as supernatants from T cell blasts, pulse-stimulated with phytohemagglutinin (PHA) or through CD3 or CD59 ligation and containing bioactive APO2L/TRAIL and/or FasL expressed on microvesicles or direct CD3 or CD59 ligation, had the same effect. Cell death was only observed in the presence of cycloheximide or after a pulse through CD3 or CD59, correlating with a net reduction in cellular Fas-associated death domain-like IL-1beta-converting enzyme-inhibitory protein long (c-FLIPL) and c-FLIPS expression. We also show that death receptor and free radical generation contribute, at least partially, to AICD induced by PHA and also to the inhibition of IL-2-dependent cell growth by CD3 or CD59 ligation. Finally, we have also shown that T cell blasts surviving PHA-induced AICD are memory CD44high cells with increased c-FLIPS and Bcl-xL expression. PMID:15653751

Bosque, Alberto; Pardo, Julián; Martínez-Lorenzo, María José; Iturralde, María; Marzo, Isabel; Piñeiro, Andrés; Alava, María Angeles; Naval, Javier; Anel, Alberto

2005-04-01

260

The Deubiquitinase CYLD Targets Smad7 Protein to Regulate Transforming Growth Factor ? (TGF-?) Signaling and the Development of Regulatory T Cells*  

PubMed Central

CYLD is a lysine 63-deubiquitinating enzyme that inhibits NF-?B and JNK signaling. Here, we show that CYLD knock-out mice have markedly increased numbers of regulatory T cells (Tregs) in peripheral lymphoid organs but not in the thymus. In vitro stimulation of CYLD-deficient naive T cells with anti-CD3/28 in the presence of TGF-? led to a marked increase in the number of Foxp3-expressing T cells when compared with stimulated naive control CD4+ cells. Under endogenous conditions, CYLD formed a complex with Smad7 that facilitated CYLD deubiquitination of Smad7 at lysine 360 and 374 residues. Moreover, this site-specific ubiquitination of Smad7 was required for activation of TAK1 and p38 kinases. Finally, knockdown of Smad7 or inhibition of p38 activity in primary T cells impaired Treg differentiation. Together, our results show that CYLD regulates TGF-? signaling function in T cells and the development of Tregs through deubiquitination of Smad7.

Zhao, Yongge; Thornton, Angela M.; Kinney, Matthew C.; Ma, Chi A.; Spinner, Jacob J.; Fuss, Ivan J.; Shevach, Ethan M.; Jain, Ashish

2011-01-01

261

The Role of Ras Guanine Nucleotide Releasing Protein 4 in Fc?RI-mediated Signaling, Mast Cell Function, and T Cell Development*  

PubMed Central

The RasGRP (Ras guanine nucleotide-releasing protein) family proteins are guanine nucleotide exchange factors that activate Ras GTPases, ultimately leading to MAPK activation and many cellular processes. The RasGRP family has four members. Published studies demonstrate that RasGRP1, RasGRP2, and RasGRP3 play critical roles in T cells, platelets, and B cells, respectively. RasGRP4 is highly expressed in mast cells. Although previous data suggest that it is important in mast cell development and function, the role of RasGRP4 in mast cells and allergic responses has not been clearly demonstrated. In this study, we generated RasGRP4?/? mice to examine the function of RasGRP4. Analyses of these mice showed that mast cells were able to develop normally in vivo and in vitro. Despite high levels of RasGRP4 expression in mast cells, RasGRP4 deficiency led to only a modest reduction in Fc?RI-mediated degranulation and cytokine production. Interestingly, mast cells deficient in both RasGRP1 and RasGRP4 had a much more severe block in Fc?RI-mediated signaling and mast cell function. We also made the unexpected finding that RasGRP4 functions during thymocyte development. Our data suggest that after the engagement of immunoreceptors, immune cells likely employ multiple members of the RasGRP family to transduce critical signals.

Zhu, Minghua; Fuller, Deirdre M.; Zhang, Weiguo

2012-01-01

262

Poor Predictive Value of Cytomegalovirus (CMV)-Specific T Cell Assays for the Development of CMV Retinitis in Patients with AIDS  

PubMed Central

Background We examined the potential clinical utility of using a cytomegalovirus (CMV)–specific T cell immunoassay to determine the risk of developing new-onset CMV retinitis (CMVR) in patients with acquired immunodeficiency syndrome (AIDS). Methods CMV-specific T cell assays were performed by multiparameter flow cytometry using stored peripheral blood mononuclear cells that had been obtained in an observational study 2–6 months before new-onset CMVR was diagnosed in case patients (at a study visit during which a dilated ophthalmologic examination revealed no evidence of CMVR) and at the same study visit in control subjects (matched by absolute CD4+ T cell count at entry) who did not subsequently develop retinitis during 1–6 years of study follow-up. Results There were no significant differences in CMV-specific CD4+ or CD8+ T cell interferon-? or interleukin-2 expression in peripheral blood mononuclear cells from case patients and control subjects. Although there were trends toward lower percentages and absolute numbers of CMV-specific, cytokine-expressing CD8+ T cells with a “late memory” phenotype (CD27?CD28?) as well as with an “early memory” phenotype (CD27+CD28+CD45RA+) in case patients than in control subjects, these differences were not statistically significant. Conclusions Many studies have reported that CMV-specific CD4+ and CD8+ T cell responses distinguish patients with active CMVR (i.e., who lack CMV-protective immunity) from those with inactive CMVR after immune restoration by antiretroviral treatment (i.e., who have CMV-protective immunity). However, the multiple CMV-specific immune responses we measured do not appear to have clinical utility for predicting the risk for patients with AIDS of developing new-onset CMVR with sufficient accuracy to be used in guiding therapeutic management.

Jacobson, Mark A.; Tan, Qi Xuan; Girling, Valerie; Poon, C.; Van Natta, Mark; Jabs, Douglas A.; Inokuma, Margaret; Maecker, Holden T.; Bredt, Barry; Sinclair, Elizabeth

2009-01-01

263

Rag expression identifies B and T cell lymphopoietic tissues during the development of common carp (Cyprinus carpio).  

PubMed

The generation of lymphoid cells during carp development was studied by analyzing expression of the recombination activating genes (rag) using in situ hybridization and real time quantitative PCR. These data were combined with immunohistochemistry using the mAb's WCL9 (cortical thymocytes) and WCI12 (B cells). Carp rag-1 and rag-2 showed 90 and 89% amino acid identity, respectively, to the corresponding zebrafish sequences. Rag-1 was first expressed in the thymus at 4 days post-fertilization (dpf), while both rag-1+/WCL9+ and rag-1-/WCL9- areas were distinguished from 1 week post-fertilization (wpf), suggesting early cortex/medulla differentiation. From 6 dpf, rag-1+ cells were also present cranio-lateral of the head kidney. From 1 wpf, rag-1/rag-2 was expressed in kidney (together with immunoglobulin heavy chain expression) but not in spleen, while WCI12+ cells appeared 1 week later in both organs, suggesting B cell recombination in kidney but not in spleen. Rag-1 expression exceeded rag-2 levels in thymus and in head- and trunk-kidney of juveniles, but this ratio was reversed in head- and trunk-kidney from approximately 16 wpf onwards. Rag-1/rag-2 expression was detected in thymi of animals over 1-year-old, but in kidney only at low levels, indicating life-long new formation of putative T cells but severely reduced formation of B cells in older fish. PMID:15967501

Huttenhuis, Heidi B T; Huising, Mark O; van der Meulen, Talitha; van Oosterhoud, Carolien N; Sánchez, Nuria Alvarez; Taverne-Thiele, Anja J; Stroband, Henri W J; Rombout, Jan H W M

2005-01-01

264

High-scatter T cells: a reliable biomarker for malignant T cells in cutaneous T-cell lymphoma  

PubMed Central

In early-stage cutaneous T-cell lymphoma (CTCL), malignant T cells are confined to skin and are difficult to isolate and discriminate from benign reactive cells. We found that T cells from CTCL skin lesions contained a population of large, high-scatter, activated skin homing T cells not observed in other inflammatory skin diseases. High-scatter T (THS) cells were CD4+ in CD4+ mycosis fungoides (MF), CD8+ in CD8+ MF, and contained only clonal T cells in patients with identifiable malignant V? clones. THS cells were present in the blood of patients with leukemic CTCL, absent in patients without blood involvement, and contained only clonal malignant T cells. The presence of clonal THS cells correlated with skin disease in patients followed longitudinally. Clonal THS cells underwent apoptosis in patients clearing on extracorporeal photopheresis but persisted in nonresponsive patients. Benign clonal T-cell proliferations mapped to the normal low-scatter T-cell population. Thus, the malignant T cells in both MF and leukemic CTCL can be conclusively identified by a unique scatter profile. This observation will allow selective study of malignant T cells, can be used to discriminate patients with MF from patients with other inflammatory skin diseases, to detect peripheral blood involvement, and to monitor responses to therapy.

Shackelton, Jeffrey B.; Watanabe, Rei; Calarese, Adam; Yamanaka, Kei-ichi; Campbell, James J.; Teague, Jessica E.; Kuo, Helen P.; Hijnen, DirkJan; Kupper, Thomas S.

2011-01-01

265

NFAT5 induction by the pre-T-cell receptor serves as a selective survival signal in T-lymphocyte development.  

PubMed

The Rel-like transcription factors nuclear factor kappa B (NF-?B) and the calcineurin-dependent nuclear factor of activated T cells (NFATc) control specific points of thymocyte maturation. Thymocytes also express a distinct member of the Rel family, the calcineurin-independent, osmostress response regulator NFAT5. Here we show that IKK? regulates the expression of NFAT5 in thymocytes, which in turn contributes to the survival of T-cell receptor ?? thymocytes and the transition from the ?-selection checkpoint to the double-positive stage in an osmostress-independent manner. NFAT5-deficient thymocytes had normal expression and proximal signaling of the pre-T-cell receptor but exhibited a partial defect in ?-chain allelic exclusion and increased apoptosis. Further analysis showed that NFAT5 regulated the expression of the prosurvival factors A1 and Bcl2 and attenuated the proapoptotic p53/Noxa axis. These findings position NFAT5 as a target of the IKK?/NF-?B pathway in thymocytes and as a downstream effector of the prosurvival role of the pre-T-cell receptor. PMID:24043824

Berga-Bolaños, Rosa; Alberdi, Maria; Buxadé, Maria; Aramburu, José; López-Rodríguez, Cristina

2013-10-01

266

NFAT5 induction by the pre-T-cell receptor serves as a selective survival signal in T-lymphocyte development  

PubMed Central

The Rel-like transcription factors nuclear factor kappa B (NF-?B) and the calcineurin-dependent nuclear factor of activated T cells (NFATc) control specific points of thymocyte maturation. Thymocytes also express a distinct member of the Rel family, the calcineurin-independent, osmostress response regulator NFAT5. Here we show that IKK? regulates the expression of NFAT5 in thymocytes, which in turn contributes to the survival of T-cell receptor ?? thymocytes and the transition from the ?-selection checkpoint to the double-positive stage in an osmostress-independent manner. NFAT5-deficient thymocytes had normal expression and proximal signaling of the pre–T-cell receptor but exhibited a partial defect in ?-chain allelic exclusion and increased apoptosis. Further analysis showed that NFAT5 regulated the expression of the prosurvival factors A1 and Bcl2 and attenuated the proapoptotic p53/Noxa axis. These findings position NFAT5 as a target of the IKK?/NF-?B pathway in thymocytes and as a downstream effector of the prosurvival role of the pre–T-cell receptor.

Berga-Bolanos, Rosa; Alberdi, Maria; Buxade, Maria; Aramburu, Jose; Lopez-Rodriguez, Cristina

2013-01-01

267

Isolation of Double Negative ?? T Cells from the Kidney.  

PubMed

There is currently no standard protocol for the isolation of DN T cells from the non-lymphoid tissues despite their increasingly reported involvement in various immune responses. DN T cells are a unique immune cell type that has been implicated in regulating immune and autoimmune responses and tolerance to allotransplants(1-6). DN T cells are, however, rare in peripheral blood and secondary lymphoid organs (spleen and lymph nodes), but are major residents of the normal kidney. Very little is known about their pathophysiologic function(7) due to their paucity in the periphery. We recently described a comprehensive phenotypic and functional analysis of this population in the kidney(8) in steady state and during ischemia reperfusion injury. Analysis of DN T cell function will be greatly enhanced by developing a protocol for their isolation from the kidney. Here, we describe a novel protocol that allows isolation of highly pure ab CD4+ CD8+ T cells and DN T cells from the murine kidney. Briefly, we digest kidney tissue using collagenase and isolate kidney mononuclear cells (KMNC) by density gradient. This is followed by two steps to enrich hematopoietic T cells from 3% to 70% from KMNC. The first step consists of a positive selection of hematopoietic cells using a CD45+ isolation kit. In the second step, DN T cells are negatively isolated by removal of non-desired cells using CD4, CD8, and MHC class II monoclonal antibodies and CD1d ?-galcer tetramer. This strategy leads to a population of more than 90% pure DN T cells. Surface staining with the above mentioned antibodies followed by FACs analysis is used to confirm purity. PMID:24893925

Martina, Maria N; Bandapalle, Samantha; Rabb, Hamid; Hamad, Abdel R

2014-01-01

268

Effects of Postchallenge Administration of ST-246 on Dissemination of IHD-J-Luc Vaccinia Virus in Normal Mice and in Immune-Deficient Mice Reconstituted with T Cells  

PubMed Central

Whole-body bioimaging was used to study dissemination of vaccinia virus (VACV) in normal and in immune deficient (nu?/nu?) mice protected from lethality by postchallenge administration of ST-246. Total fluxes were recorded in the liver, spleen, lungs, and nasal cavities of live mice after intranasal infection with a recombinant IHD-J-Luc VACV expressing luciferase. Areas under the flux curve were calculated for individual mice to assess viral loads. Treatment for 2 to 5 days of normal BALB/c mice with ST-246 at 100 mg/kg starting 24 h postchallenge conferred 100% protection and reduced viral loads in four organs compared to control mice. Mice also survived after 5 days of treatment with ST-246 at 30 mg/kg, and yet the viral loads and poxes were higher in these mice compared to 100-mg/kg treatment group. Nude mice were not protected by ST-246 alone or by 10 million adoptively transferred T cells. In contrast, nude mice that received T cells and 7-day treatment with ST-246 survived infection and exhibited reduced viral loads compared to nonreconstituted and ST-246-treated mice after ST-246 was stopped. Similar protection of nude mice was achieved using adoptively transferred 1.0 and 0.1 million, but not 0.01 million, purified T cells or CD4+ or CD8+ T cells in conjunction with ST-246 treatment. These data suggest that ST-246 protects immunocompetent mice from lethality and reduces viral dissemination in internal organs and poxvirus lesions. Furthermore, immune-deficient animals with partial T cell reconstitution can control virus replication after a course of ST-246 and survive lethal vaccinia virus challenge.

Shotwell, Elisabeth; Scott, John; Cruz, Stephanie; King, Lisa R.; Manischewitz, Jody; Diaz, Claudia G.; Jordan, Robert A.; Grosenbach, Douglas W.; Golding, Hana

2013-01-01

269

The Role of Intercellular Adhesion Molecule1 (ICAM-1), Vascular Cell Adhesion Molecule1 (VCAM-1), and Regulated on Activation, Normal T-Cell Expressed and Secreted (RANTES) in the Relationship between Air Pollution and Asthma among Children  

Microsoft Academic Search

To evaluate the role of adhesion molecules and chemokines in the relationship between air pollution and asthma, the authors determined the following in 230 children who lived in 4 communities in Japan that had different levels of air pollution: serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1); soluble vascular cell adhesion molecule-1 (sVCAM-1); regulated on activation, normal T-cell expressed and

Michiko Ando; Masayuki Shima; Motoaki Adachi; Yoshizo Tsunetoshi

2001-01-01

270

T Cell-Dendritic Cell Interaction in Vivo: Random Encounters Favor Development of Long-Lasting Ties  

NSDL National Science Digital Library

Understanding the complexity of the functional communication between cells composing the immune system is central to improving our capacity to manipulate it and conceive better strategies to combat microbial pathogens. So far, these studies have been based on immunohistochemistry of fixed tissues and in vitro attempts to reproduce functional connections between cells. The application of two-photon laser microscopy to the observation of viable immune cells in their natural environment where foreign antigens are carried to trigger an immune response opens a new era for these studies. They reveal exceptional properties of the locomotion of T cells that facilitate encounters with dendritic cells and the receipt of information that promotes T cell survival, death, or initiation of immune responses. These studies also complement in vitro observations addressing the importance of time of stimulation in determining T cell fates.

Oreste Acuto (Institut Pasteur;Molecular Immunology Unit, Department of Immunology REV)

2003-07-22

271

Gene enrichment profiles reveal T-cell development, differentiation, and lineage-specific transcription factors including ZBTB25 as a novel NF-AT repressor  

PubMed Central

The identification of transcriptional regulatory networks, which control tissue-specific development and function, is of central importance to the understanding of lymphocyte biology. To decipher transcriptional networks in T-cell development and differentiation we developed a browsable expression atlas and applied a novel quantitative method to define gene sets most specific to each of the represented cell subsets and tissues. Using this system, body atlas size datasets can be used to examine gene enrichment profiles from a cell/tissue perspective rather than gene perspective, thereby identifying highly enriched genes within a cell type, which are often key to cellular differentiation and function. A systems analysis of transcriptional regulators within T cells during different phases of development and differentiation resulted in the identification of known key regulators and uncharacterized coexpressed regulators. ZBTB25, a BTB-POZ family transcription factor, was identified as a highly T cell–enriched transcription factor. We provide evidence that ZBTB25 functions as a negative regulator of nuclear factor of activated T cells (NF-AT) activation, such that RNA interference mediated knockdown resulted in enhanced activation of target genes. Together, these findings suggest a novel mechanism for NF-AT mediated gene expression and the compendium of expression data provides a quantitative platform to drive exploration of gene expression across a wide range of cell/tissue types.

Benita, Yair; Cao, Zhifang; Giallourakis, Cosmas; Li, Chun; Gardet, Agnes

2010-01-01

272

Multilayered specification of the T-cell lineage fate  

PubMed Central

Summary T-cell development from stem cells has provided a highly accessible and detailed view of the regulatory processes that can go into the choice of a cell fate in a postembryonic, stem cell-based system. But, it has been a view from the outside. The problems in understanding the regulatory basis for this lineage choice begin with the fact that too many transcription factors are needed to provide crucial input: without any one of them, T-cell development fails. Furthermore, almost all the factors known to provide crucial functions during the climax of T-lineage commitment itself are also vital for earlier functions that establish the pool of multilineage precursors that would normally feed into the T-cell specification process. When the regulatory genes that encode them are mutated, the confounding effects on earlier stages make it difficult to dissect T-cell specification genetically. Yet both the positive and the negative regulatory events involved in the choice of a T-cell fate are actually a mosaic of distinct functions. New evidence has emerged recently that finally provides a way to separate the major components that fit together to drive this process. Here, we review insights into T-cell specification and commitment that emerge from a combination of molecular, cellular, and systems biology approaches. The results reveal the regulatory structure underlying this lineage decision.

Rothenberg, Ellen V.; Zhang, Jingli; Li, Long

2010-01-01

273

?? T Cells and Their Potential for Immunotherapy  

PubMed Central

V?9V?2 (also termed V?2V?2) T cells, a major human peripheral blood ?? T cell subset, recognize microbial (E)-4-hydroxy-3-methylbut-2-enyl diphosphate and endogenous isopentenyl diphosphate in a TCR-dependent manner. The recognition does not require specific accessory cells, antigen uptake, antigen processing, or MHC class I, class II, or class Ib expression. This subset of T cells plays important roles in mediating innate immunity against a wide variety of infections and displays potent and broad cytotoxic activity against human tumor cells. Because ??T cells express both natural killer receptors such as NKG2D and ?? T cell receptors, they are considered to represent a link between innate and adaptive immunity. In addition, activated ?? T cells express a high level of antigen-presenting cell-related molecules and can present peptide antigens derived from destructed cells to ?? T cells. Utilizing these antimicrobial and anti-tumor properties of ?? T cells, preclinical and clinical trials have been conducted to develop novel immunotherapies for infections and malignancies. Here, we review the immunological properties of ?? T cells including the underlying recognition mechanism of nonpeptitde antigens and summarize the results of ?? T cell-based therapies so far performed. Based on the results of the reported trials, ?? T cells appear to be a promising tool for novel immunotherapies against certain types of diseases.

Wu, Yan-Ling; Ding, Yan-Ping; Tanaka, Yoshimasa; Shen, Li-Wen; Wei, Chuan-He; Minato, Nagahiro; Zhang, Wen

2014-01-01

274

Bach2 maintains T cells in a naive state by suppressing effector memory-related genes  

PubMed Central

The transcriptional repressor BTB and CNC homology 2 (Bach2) is thought to be mainly expressed in B cells with specific functions such as class switch recombination and somatic hypermutation, but its function in T cells is not known. We found equal Bach2 expression in T cells and analyzed its function using Bach2-deficient (?/?) mice. Although T-cell development was normal, numbers of peripheral naive T cells were decreased, which rapidly produced Th2 cytokines after TCR stimulation. Bach2?/? naive T cells highly expressed genes related to effector-memory T cells such as CCR4, ST-2 and Blimp-1. Enhanced expression of these genes induced Bach2?/? naive T cells to migrate toward CCR4-ligand and respond to IL33. Forced expression of Bach2 restored the expression of these genes. Using Chromatin Immunoprecipitation (ChIP)-seq analysis, we identified S100 calcium binding protein a, Heme oxigenase 1, and prolyl hydroxylase 3 as Bach2 direct target genes, which are highly expressed in effector-memory T cells. These findings indicate that Bach2 suppresses effector memory-related genes to maintain the naive T-cell state and regulates generation of effector-memory T cells.

Tsukumo, Shin-ichi; Unno, Midori; Muto, Akihiko; Takeuchi, Arata; Kometani, Kohei; Kurosaki, Tomohiro; Igarashi, Kazuhiko; Saito, Takashi

2013-01-01

275

Bach2 maintains T cells in a naive state by suppressing effector memory-related genes.  

PubMed

The transcriptional repressor BTB and CNC homology 2 (Bach2) is thought to be mainly expressed in B cells with specific functions such as class switch recombination and somatic hypermutation, but its function in T cells is not known. We found equal Bach2 expression in T cells and analyzed its function using Bach2-deficient (-/-) mice. Although T-cell development was normal, numbers of peripheral naive T cells were decreased, which rapidly produced Th2 cytokines after TCR stimulation. Bach2(-/-) naive T cells highly expressed genes related to effector-memory T cells such as CCR4, ST-2 and Blimp-1. Enhanced expression of these genes induced Bach2(-/-) naive T cells to migrate toward CCR4-ligand and respond to IL33. Forced expression of Bach2 restored the expression of these genes. Using Chromatin Immunoprecipitation (ChIP)-seq analysis, we identified S100 calcium binding protein a, Heme oxigenase 1, and prolyl hydroxylase 3 as Bach2 direct target genes, which are highly expressed in effector-memory T cells. These findings indicate that Bach2 suppresses effector memory-related genes to maintain the naive T-cell state and regulates generation of effector-memory T cells. PMID:23754397

Tsukumo, Shin-ichi; Unno, Midori; Muto, Akihiko; Takeuchi, Arata; Kometani, Kohei; Kurosaki, Tomohiro; Igarashi, Kazuhiko; Saito, Takashi

2013-06-25

276

CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2  

Microsoft Academic Search

Efficient generation of regulatory T cells (Treg cells) in the thymus requires CD28 costimulation, but it is not known why. Here, molecular mapping of CD28 costimulation showed that Treg cell generation requires a motif that binds the tyrosine kinase Lck, precisely the same motif that is required for CD28 costimulation of interleukin 2 production. Nevertheless, CD28 costimulation provides more than

Xuguang Tai; Michelle Cowan; Lionel Feigenbaum; Alfred Singer

2005-01-01

277

HCV-infected hepatocytes drive CD4+ CD25+ Foxp3+ regulatory T-cell development through the Tim-3/Gal-9 pathway.  

PubMed

HCV is remarkable at disrupting human immunity to establish chronic infection. The accumulation of Treg cells at the site of infection and upregulation of inhibitory signaling pathways (such as T-cell Ig and mucin domain protein-3 (Tim-3) and galectin-9 (Gal-9)) play pivotal roles in suppressing antiviral effector T (Teff) cells that are essential for viral clearance. While Tim-3/Gal-9 interactions have been shown to negatively regulate Teff cells, their role in regulating Treg cells is poorly understood. To explore how Tim-3/Gal-9 interactions regulate HCV-mediated Treg-cell development, here we provide pilot data showing that HCV-infected human hepatocytes express higher levels of Gal-9 and TGF-?, and upregulate Tim-3 expression and regulatory cytokines TGF-?/IL-10 in co-cultured human CD4(+) T cells, driving conventional CD4(+) T cells into CD25(+) Foxp3(+) Treg cells. Additionally, recombinant Gal-9 protein can transform TCR-activated CD4(+) T cells into Foxp3(+) Treg cells in a dose-dependent manner. Importantly, blocking Tim-3/Gal-9 ligations abrogates HCV-mediated Treg-cell induction by HCV-infected hepatocytes, suggesting that Tim-3/Gal-9 interactions may regulate human Foxp3(+) Treg-cell development and function during HCV infection. PMID:23161469

Ji, Xiao J; Ma, Cheng J; Wang, Jia M; Wu, Xiao Y; Niki, Toshiro; Hirashima, Mitsumi; Moorman, Jonathan P; Yao, Zhi Q

2013-02-01

278

Harnessing endogenous miR-181a to segregate transgenic antigen receptor expression in developing versus post-thymic T cells in murine hematopoietic chimeras.  

PubMed

MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression by targeting complementary sequences, referred to as miRNA recognition elements (MREs), typically located in the 3' untranslated region of mRNAs. miR-181a is highly expressed in developing thymocytes and markedly downregulated in post-thymic T cells. We investigated whether endogenous miR-181a can be harnessed to segregate expression of chimeric antigen receptors (CARs) and TCRs between developing and mature T cells. Lentiviral-encoded antigen receptors were tagged with a miR-181a-specific MRE and transduced into mouse BM cells that were used to generate hematopoietic chimeras. Expression of a CAR specific for human CD19 (hCD19) was selectively suppressed in late double-negative and double-positive thymocytes, coinciding with the peak in endogenous miR-181a expression. Receptor expression was fully restored in post-thymic resting and activated T cells, affording protection against a subsequent challenge with hCD19+ tumors. Hematopoietic mouse chimeras engrafted with a conalbumin-specific TCR prone to thymic clonal deletion acquired peptide-specific T cell responsiveness only when the vector-encoded TCR transcript was similarly engineered to be subject to regulation by miR-181a. These results demonstrate the potential of miRNA-regulated transgene expression in stem cell-based therapies, including cancer immunotherapy. PMID:19033646

Papapetrou, Eirini P; Kovalovsky, Damian; Beloeil, Laurent; Sant'angelo, Derek; Sadelain, Michel

2009-01-01

279

Genetic modification of T cell clones to improve the safety and efficacy of adoptive T cell therapy.  

PubMed

Our laboratory has developed methods to isolate human antigen-specific cytolytic CD8+ T cell clones and to expand such clones in vitro to numbers sufficient for T cell therapy of human diseases. Studies in immunocompromised bone marrow transplant patients at high risk for disease associated with cytomegalovirus have demonstrated that administration of more than 10(9) CD8+ T cell clones is safe and can effectively reconstitute a deficient human immune response. Our laboratory is applying this strategy of adoptive therapy to the treatment of human cancer, starting with the subset of patients with Hodgkin's disease who show expression of proteins encoded by the Epstein-Barr virus in their malignant Reed-Sternberg cells. The development of efficient systems such as retroviral vectors for the introduction of genes into primary cells has made it possible to consider overcoming some of the limitations of the effector T cells that normally mediate response to an antigen. Our laboratory is attempting to modify T cell clones by the introduction of genes before transfer as a means to improve the safety and/or efficacy of T cell therapy. PMID:7796672

Greenberg, P D; Nelson, B; Gilbert, M; Sing, A; Yee, C; Jensen, M; Riddell, S R

1994-01-01

280

The Type of Responder T-Cell Has a Significant Impact in a Human In Vitro Suppression Assay  

PubMed Central

Background In type 1 diabetes (T1D), a prototypic autoimmune disease, effector T cells destroy beta cells. Normally, CD4+CD25+high, or natural regulatory T cells (Tregs), counter this assault. In autoimmunity, the failure to suppress CD4+CD25low T cells is important for disease development. However, both Treg dysfunction and hyperactive responder T-cell proliferation contribute to disease. Methods/Principal Findings We investigated human CD4+CD25low T cells and compared them to CD4+CD25- T cells in otherwise equivalent in vitro proliferative conditions. We then asked whether these differences in suppression are exacerbated in T1D. In both single and co-culture with Tregs, the CD4+CD25low T cells divided more rapidly than CD4+CD25- T cells, which manifests as increased proliferation/reduced suppression. Time-course experiments showed that this difference could be explained by higher IL-2 production from CD4+CD25low compared to CD4+CD25- T cells. There was also a significant increase in CD4+CD25low T-cell proliferation compared to CD4+CD25- T cells during suppression assays from RO T1D and at-risk subjects (n?=?28, p?=?0.015 and p?=?0.024 respectively). Conclusions/Significance The in vitro dual suppression assays proposed here could highlight the impaired sensitivity of certain responder T cells to the suppressive effect of Tregs in human autoimmune diseases.

Jana, Srikanta; Campbell, Hope; Woodliff, Jeffrey; Waukau, Jill; Jailwala, Parthav; Ghorai, Jugal; Ghosh, Soumitra; Glisic, Sanja

2010-01-01

281

Understanding signaling pathways regulating CD4 + T cell effector function  

Microsoft Academic Search

Our laboratory is interested in the signaling pathways that regulate the T cell development and differentiation required for successful responses to diverse immune challenges. We are currently examining the role of the Tec kinases and T cell receptor signaling in regulating distinct types of T cell development in the thymus leading to the selection and maturation of conventional T cells

Jennifer L. Cannons; Julio Gomez-Rodriguez; Hai Qi; Kristina Lu; Kristen L. Mueller; Reiko Horai; Ana M. Venegas; Robin Blair; Ronald Germain; Pamela L. Schwartzberg

2009-01-01

282

The development of transplant coronary artery disease after cardiac transplantation is correlated with a predominance of CD8+ T lymphocytes in endomyocardial biopsy derived T cell cultures.  

PubMed Central

Long-term survival of heart transplant recipients is limited by the development of transplant coronary artery disease (TCAD). We analysed whether the development of TCAD is correlated with the incidence of acute rejection episodes, with the formation of anti-HLA antibodies or with the composition and function of T lymphocyte cultures derived from endomyocardial biopsies. TCAD was assessed by visual analysis of annually performed coronary angiograms and defined as the presence of all vascular changes, including minor wall irregularities. One year after transplantation, 31 of the 77 patients studied had TCAD (40%). The median age and mean number of HLA mismatches in patients with or without TCAD were highly comparable. The patient groups did not differ in incidence of acute rejection episodes, nor in percentage of endomyocardial biopsies yielding T cell cultures. At 1 year after transplantation, lymphocyte cultures from 18/31 TCAD+ patients (58%) and 27/46 TCAD- patients (57%) were analysed. The TCAD+ patients had, compared with the TCAD- patients, a higher median percentage of CD8+ T cells (71% versus 25%, P = 0.06) and a lower median percentage of CD4+ T cells (4% versus 40%, P = 0.04). Similar differences were found in a longitudinal analysis of the culture results of endomyocardial biopsies (EMBs) obtained during the first year. The cytotoxic reactivity of the cultures against donor HLA class I or class II antigens was comparable in the two groups, although a difference in recognition of heart specific antigens remains possible. The fact that EMB-derived cultures from TCAD+ and TCAD- patients differed in T cell phenotype populations gives some support to the hypothesis that cellular immunological processes are involved in the development of TCAD. However, while the median values differed, the overlap of the percentages of CD8+ cells in cultures from TCAD- and TCAD+ patients shows that other factors besides CD8+ T cells also play a role.

Jutte, N H; Groeneveld, K; Balk, A H; Ouwehand, A J; Loonen, E H; Van der Linden, M; Strikwerda, S; Mochtar, B; Claas, F H; Weimar, W

1994-01-01

283

SOCS3 deletion in T lymphocytes suppresses development of chronic ocular inflammation via upregulation of CTLA-4 and expansion of regulatory T cells.  

PubMed

Suppressors of cytokine signaling (SOCS) proteins are negative-feedback regulators of the JAK/STAT pathway, and SOCS3 contributes to host immunity by regulating the intensity and duration of cytokine signals and inflammatory responses. Mice with Socs3 deletion in myeloid cells exhibit enhanced STAT3 signaling, expansion of Th1 and Th17 cells, and develop severe experimental autoimmune encephalomyelitis. Interestingly, development of the unique IL-17/IFN-? double-producing (Th17/IFN-? and Tc17/IFN-?) subsets that exhibit strong cytotoxic activities and are associated with pathogenesis of several autoimmune diseases has recently been shown to depend on epigenetic suppression of SOCS3 expression, further suggesting involvement of SOCS3 in autoimmunity and tumor immunity. In this study, we generated mice with Socs3 deletion in the CD4 T cell compartment (CD4-SOCS3 knockout [KO]) to determine in vivo effects of the loss of Socs3 in the T cell-mediated autoimmune disease, experimental autoimmune uveitis (EAU). In contrast to the exacerbation of experimental autoimmune encephalomyelitis in myeloid-specific SOCS3-deleted mice, CD4-SOCS3KO mice were protected from acute and chronic uveitis. Protection from EAU correlated with enhanced expression of CTLA-4 and expansion of IL-10-producing regulatory T cells with augmented suppressive activities. We further show that SOCS3 interacts with CTLA-4 and negatively regulates CTLA-4 levels in T cells, providing a mechanistic explanation for the expansion of regulatory T cells in CD4-SOCS3 during EAU. Contrary to in vitro epigenetic studies, Th17/IFN-? and Tc17/IFN-? populations were markedly reduced in CD4-SOCS3KO, suggesting that SOCS3 promotes expansion of the Th17/IFN-? subset associated with development of severe uveitis. Thus, SOCS3 is a potential therapeutic target in uveitis and other autoinflammatory diseases. PMID:24101549

Yu, Cheng-Rong; Kim, Sung-Hye; Mahdi, Rashid M; Egwuagu, Charles E

2013-11-15

284

Foxp3+ CD25+ regulatory T cells specific for a neo-self-antigen develop at the double-positive thymic stage  

PubMed Central

Thymus-derived regulatory T cells (Tregs) expressing CD4, CD25, and the transcription factor Foxp3 play major roles in preventing autoimmunity. The Treg population is enriched in T cells expressing high-avidity self-reactive T cell receptors, and thymic epithelial cells expressing self-antigens (Ag) have been implicated in their induction and/or selection. However, the thymic selection events leading to Treg lineage commitment remain unclear. We followed the thymic development of self-Ag-specific Tregs in double-transgenic mice coexpressing a neo-self-Ag, hemagglutinin (HA) under the control of a neural tissue-specific promoter, and a transgenic class II-restricted T cell antigen receptor specific for HA111-119. Our data show that the promiscuous expression of the HA transgene in thymic epithelial cells is involved in the selective induction and/or expansion of HA-specific Foxp3+ Treg thymic precursors as early as the double-positive stage.

Cabarrocas, Julie; Cassan, Cecile; Magnusson, Fay; Piaggio, Eliane; Mars, Lennart; Derbinski, Jens; Kyewski, Bruno; Gross, David-Alexandre; Salomon, Benoit L.; Khazaie, Khashayarsha; Saoudi, Abdelhadi; Liblau, Roland S.

2006-01-01

285

Ex Vivo Expansion of Human CD8+ T Cells Using Autologous CD4+ T Cell Help  

PubMed Central

Background Using in vivo mouse models, the mechanisms of CD4+ T cell help have been intensively investigated. However, a mechanistic analysis of human CD4+ T cell help is largely lacking. Our goal was to elucidate the mechanisms of human CD4+ T cell help of CD8+ T cell proliferation using a novel in vitro model. Methods/Principal Findings We developed a genetically engineered novel human cell-based artificial APC, aAPC/mOKT3, which expresses a membranous form of the anti-CD3 monoclonal antibody OKT3 as well as other immune accessory molecules. Without requiring the addition of allogeneic feeder cells, aAPC/mOKT3 enabled the expansion of both peripheral and tumor-infiltrating T cells, regardless of HLA-restriction. Stimulation with aAPC/mOKT3 did not expand Foxp3+ regulatory T cells, and expanded tumor infiltrating lymphocytes predominantly secreted Th1-type cytokines, interferon-? and IL-2. In this aAPC-based system, the presence of autologous CD4+ T cells was associated with significantly improved CD8+ T cell expansion in vitro. The CD4+ T cell derived cytokines IL-2 and IL-21 were necessary but not sufficient for this effect. However, CD4+ T cell help of CD8+ T cell proliferation was partially recapitulated by both adding IL-2/IL-21 and by upregulation of IL-21 receptor on CD8+ T cells. Conclusions We have developed an in vitro model that advances our understanding of the immunobiology of human CD4+ T cell help of CD8+ T cells. Our data suggests that human CD4+ T cell help can be leveraged to expand CD8+ T cells in vitro.

Butler, Marcus O.; Imataki, Osamu; Yamashita, Yoshihiro; Tanaka, Makito; Ansen, Sascha; Berezovskaya, Alla; Metzler, Genita; Milstein, Matthew I.; Mooney, Mary M.; Murray, Andrew P.; Mano, Hiroyuki; Nadler, Lee M.; Hirano, Naoto

2012-01-01

286

Lymphoproliferative defects in mice lacking the expression of neurofibromin: functional and biochemical consequences of Nf1 deficiency in T-cell development and function  

Microsoft Academic Search

Ras plays an essential role in lymphocyte development and function. However, in vivo consequence(s) of regulation of Ras activity by guanosine triphosphatase (GTPase)-activating proteins (GAPs) on lymphocyte development and function are not known. In this study we demonstrate that neurofibromin, the protein encoded by the NF1 tumor suppressor gene func- tions as a GAP for Ras in T cells. Loss

David A. Ingram; Lei Zhang; Jennifer McCarthy; Mary Jo Wenning; Lucy Fisher; Feng-Chun Yang; D. Wade Clapp; Reuben Kapur

2002-01-01

287

T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays  

Microsoft Academic Search

Chemicals can elicit T-cell-mediated diseases such as allergic contact dermatitis and adverse drug reactions. Therefore, testing\\u000a of chemicals, drugs and protein allergens for hazard identification and risk assessment is essential in regulatory toxicology.\\u000a The seventh amendment of the EU Cosmetics Directive now prohibits the testing of cosmetic ingredients in mice, guinea pigs\\u000a and other animal species to assess their sensitizing

Stefan F. Martin; Philipp R. Esser; Sonja Schmucker; Lisa Dietz; Dean J. Naisbitt; B. Kevin Park; Marc Vocanson; Jean-Francois Nicolas; Monika Keller; Werner J. Pichler; Matthias Peiser; Andreas Luch; Reinhard Wanner; Enrico Maggi; Andrea Cavani; Thomas Rustemeyer; Anne Richter; Hermann-Josef Thierse; Federica Sallusto

2010-01-01

288

Development of a coordinated allo T cell and auto B cell response against autosomal PTK2B after allogeneic hematopoietic stem cell transplantation.  

PubMed

It is well known that allo-reactive T cells play a crucial role in graft-versus-leukemia and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (alloSCT). Allo-reactive CD4(+) T cells can mediate direct cytolysis, but may also stimulate production of IgG antibodies as helper cells. Immune complexes may subsequently be processed and presented by professional antigen presenting cells and stimulate induction of specific CD8(+) T cells. As such, proteins targeted in coordinated T- and B-cell responses may represent a class of immunodominant antigens in clinical responses after alloSCT. We previously identified LB-PTK2B-1T as HLA class II restricted polymorphic antigen in a patient treated with donor lymphocyte infusion for relapsed chronic myeloid leukemia after HLA-matched alloSCT. Since PTK2B has also been described as antibody target, we here investigated whether a coordinated T- and B-cell response against PTK2B was induced. Patient serum before and after alloSCT and donor lymphocyte infusion (DLI) was screened for antibodies, and we indeed observed development of a humoral immune response against PTK2B. Antibodies against PTK2B were only found after DLI and, in contrast to the CD4(+) T cells, recognized a monomorphic region of the protein. To our knowledge, this is the first description of a coordinated allo-reactive CD4(+) T-cell and auto-reactive antibody response against an autosomal antigen. PMID:24097630

Kremer, Anita N; van der Griendt, Judith C; van der Meijden, Edith D; Honders, M Willy; Ayoglu, Burcu; Schwenk, Jochen M; Nilsson, Peter; Falkenburg, J H Frederik; Griffioen, Marieke

2014-02-01

289

Mitomycin C-treated dendritic cells inactivate autoreactive T cells: Toward the development of a tolerogenic vaccine in autoimmune diseases  

PubMed Central

Treatment of autoimmune diseases remains a challenge for immunological research. An ideal therapy should inhibit the immune reaction against the diseased organ and leave the rest of the immune response intact. Our previous studies showed that donor-derived dendritic cells (DCs) treated in vitro with mitomycin C (MMC) suppress rat heart allograft rejection if injected into recipients before transplantation. Here we analyze their efficacy in controlling autoimmunity. MMC-DCs loaded with myelin-basic-protein (MBP) inhibited specific T cells derived from multiple sclerosis patients in vitro. If coincubated with MMC-DCs, T cells were arrested in the G0/G1 cell cycle phase. Microarray gene scan showed that MMC influences the expression of 116 genes in DCs, one main cluster comprising apoptotic and the second cluster immunosuppressive genes. Apparently, the combination of apoptosis with expression of tolerogenic molecules renders MMC-DCs suppressive. MBP-loaded MMC-DCs also inhibited mouse T cells in vitro and, in contrast to MBP-loaded naïve DCs, did not induce experimental autoimmune encephalitis. Most importantly, mice vaccinated with inhibitory DCs became resistant to the disease. Whereas this is not the first report on generation of suppressive DCs, it delineates a method using a clinically approved drug at nontoxic concentrations, which yields irreversibly changed DCs, effective across species in vitro and in vivo.

Terness, Peter; Oelert, Thilo; Ehser, Sandra; Chuang, Jing Jing; Lahdou, Imad; Kleist, Christian; Velten, Florian; Hammerling, Gunter J.; Arnold, Bernd; Opelz, Gerhard

2008-01-01

290

Mitomycin C-treated dendritic cells inactivate autoreactive T cells: toward the development of a tolerogenic vaccine in autoimmune diseases.  

PubMed

Treatment of autoimmune diseases remains a challenge for immunological research. An ideal therapy should inhibit the immune reaction against the diseased organ and leave the rest of the immune response intact. Our previous studies showed that donor-derived dendritic cells (DCs) treated in vitro with mitomycin C (MMC) suppress rat heart allograft rejection if injected into recipients before transplantation. Here we analyze their efficacy in controlling autoimmunity. MMC-DCs loaded with myelin-basic-protein (MBP) inhibited specific T cells derived from multiple sclerosis patients in vitro. If coincubated with MMC-DCs, T cells were arrested in the G(0)/G(1) cell cycle phase. Microarray gene scan showed that MMC influences the expression of 116 genes in DCs, one main cluster comprising apoptotic and the second cluster immunosuppressive genes. Apparently, the combination of apoptosis with expression of tolerogenic molecules renders MMC-DCs suppressive. MBP-loaded MMC-DCs also inhibited mouse T cells in vitro and, in contrast to MBP-loaded naïve DCs, did not induce experimental autoimmune encephalitis. Most importantly, mice vaccinated with inhibitory DCs became resistant to the disease. Whereas this is not the first report on generation of suppressive DCs, it delineates a method using a clinically approved drug at nontoxic concentrations, which yields irreversibly changed DCs, effective across species in vitro and in vivo. PMID:19017789

Terness, Peter; Oelert, Thilo; Ehser, Sandra; Chuang, Jing Jing; Lahdou, Imad; Kleist, Christian; Velten, Florian; Hämmerling, Günter J; Arnold, Bernd; Opelz, Gerhard

2008-11-25

291

Engineered T cells for cancer treatment.  

PubMed

Adoptively transferred T cells have the capacity to traffic to distant tumor sites, infiltrate fibrotic tissue and kill antigen-expressing tumor cells. Various groups have investigated different genetic engineering strategies designed to enhance tumor specificity, increase T cell potency, improve proliferation, persistence or migratory capacity and increase safety. This review focuses on recent developments in T cell engineering, discusses the clinical application of these engineered cell products and outlines future prospects for this therapeutic modality. PMID:24239105

Anurathapan, Usanarat; Leen, Ann M; Brenner, Malcolm K; Vera, Juan F

2014-06-01

292

Cutaneous T Cell Lymphoma  

MedlinePLUS

... cutaneous CD4+ small/medium pleomorphic T-cell lymphoma Aggressive clinical behavior l Sézary syndrome l Primary cutaneous ... lymphoma l Primary cutaneous follicle center lymphoma Intermediate-aggressive clinical behavior l Primary cutaneous diffuse large B- ...

293

Mst1/Mst2 regulate development and function of regulatory T cells through modulation of Foxo1/Foxo3 stability in autoimmune disease.  

PubMed

Foxp3 expression and regulatory T cell (Treg) development are critical for maintaining dominant tolerance and preventing autoimmune diseases. Human MST1 deficiency causes a novel primary immunodeficiency syndrome accompanied by autoimmune manifestations. However, the mechanism by which Mst1 controls immune regulation is unknown. In this article, we report that Mst1 regulates Foxp3 expression and Treg development/function and inhibits autoimmunity through modulating Foxo1 and Foxo3 (Foxo1/3) stability. We have found that Mst1 deficiency impairs Foxp3 expression and Treg development and function in mice. Mechanistic studies reveal that Mst1 enhances Foxo1/3 stability directly by phosphorylating Foxo1/3 and indirectly by attenuating TCR-induced Akt activation in peripheral T cells. Our studies have also shown that Mst1 deficiency does not affect Foxo1/3 cellular localization in CD4 T cells. In addition, we show that Mst1(-/-) mice are prone to autoimmune disease, and mutant phenotypes, such as overactivation of naive T cells, splenomegaly, and autoimmune pathological changes, are suppressed in Mst1(-/-) bone marrow chimera by cotransplanted wt Tregs. Finally, we demonstrate that Mst1 and Mst2 play a partially redundant role in Treg development and autoimmunity. Our findings not only identify Mst kinases as the long-searched-for factors that simultaneously activate Foxo1/3 and inhibit TCR-stimulated Akt downstream of TCR signaling to promote Foxp3 expression and Treg development, but also shed new light on understanding and designing better therapeutic strategies for MST1 deficiency-mediated human immunodeficiency syndrome. PMID:24453252

Du, Xingrong; Shi, Hao; Li, Jiang; Dong, Yongli; Liang, JieLiang; Ye, Jian; Kong, Shanshan; Zhang, Shujing; Zhong, Tao; Yuan, Zengqiang; Xu, Tian; Zhuang, Yuan; Zheng, Biao; Geng, Jian-Guo; Tao, Wufan

2014-02-15

294

T cell responses in lymph nodes.  

PubMed

Activation of T cells by antigen-presenting cells (APCs) in lymph nodes (LNs) is a key initiating event in many immune responses. Our understanding of this process has been both improved and complicated in recent years by evidence from techniques such as intravital microscopy that has revealed new levels of dynamism in the interaction of T cells and APCs. In particular, the complex motility of T cells within LNs, and their serial interactions with many APCs, imply that earlier static models of T cell activation need to be updated. Here we review the first attempts to model T cell interactions with APCs in LNs that incorporate simulations of T cell motility, based on experimental observations. We show that lattice-based modeling approaches are the dominant trend in these models, and then chart a possible course for development of these models toward spatially-resolved models of immune responses within LNs. PMID:20836014

Bogle, Gib; Dunbar, P Rod

2010-01-01

295

Involvement of transcription factors TCF-1 and GATA-3 in the initiation of the earliest step of T cell development in the thymus  

PubMed Central

Flow cytometric and immunocytochemical analyses of murine fetal thymus (FT) cells with antibodies to various surface markers and transcription factors reveal that the synthesis of TCF-1 and GATA-3 protein begins simultaneously in a fraction of the most immature population of FT cells, which have the phenotype of CD4-CD8-CD44+CD25-. No TCF-1- producing cells is found in the fetal liver (FL). In CD44+CD25- FT cells, the production of TCF-1 is immediately followed by intracellular expression of CD3 epsilon. It is also found that the T cell development from FL, but not FT, progenitors in the FT organ culture system is severely inhibited by the addition of antisense oligonucleotides for either TCF-1 or GATA-3. These results strongly suggest that TCF-1 and GATA-3 play essential roles in the initiation of the earliest steps of T cell development in the thymus.

1996-01-01

296

Use of a microgravity organ culture dish system to demonstrate the signal dampening effects of modeled microgravity during T cell development.  

PubMed

Recently, we have shown that exposure of fetal thymus organ cultures (FTOC) to modeled microgravity (MMG) using a clinostat with a microgravity organ culture dish system (MOCDS) blocks T cell development in a manner independent of steroid stress hormones present in vivo. In this study, we describe the development of the MOCDS system, as well as its use in attempting to understand the mechanism by which T cell development is inhibited in MMG. We show that after MMG exposure FTOC exhibited a significant reduction in CD4+CD8+ double positive (DP) cell production, but those DP cells which remained expressed higher levels of the T cell receptor (TCR) associated molecule, CD3. Interestingly, CD4-CD8- double negative (DN) cells expressed lower levels of CD3 on their surface. DN, as well as immature single positive (ISP) cells, also expressed reduced levels of the IL-7 receptor alpha chain (CD127). These changes in CD3 and CD127 expression were concomitantly associated with an increased production of tumor necrosis factor (TNF)-alpha. We were also able to show that addition of an exogenous signal (anti-CD3epsilon monoclonal antibody) to these cultures effectively mitigated the MMG-induced effects, suggesting that MMG-exposure causes a signal dampening effect on developing thymocytes. PMID:15752552

Woods, Chris C; Banks, Krista E; Lebsack, Ty W; White, Todd C; Anderson, Grant A; Maccallum, Taber; Gruener, Raphael; DeLuca, Dominick

2005-01-01

297

Pushing the frontiers of T-cell vaccines: accurate measurement of human T-cell responses  

PubMed Central

There is a need for novel approaches to tackle major vaccine challenges such as malaria, tuberculosis and HIV, among others. Success will require vaccines able to induce a cytotoxic T-cell response – a deficiency of most current vaccine approaches. The successful development of T-cell vaccines faces many hurdles, not least being the lack of consensus on a standardized T-cell assay format able to be used as a correlate of vaccine efficacy. Hence, there remains a need for reproducible measures of T-cell immunity proven in human clinical trials to correlate with vaccine protection. The T-cell equivalent of a neutralizing antibody assay would greatly accelerate the development and commercialization of T-cell vaccines. Recent advances have seen a plethora of new T-cell assays become available, including some like cytometry by time-of-flight with extreme multiparameter T-cell phenotyping capability. However, whether it is historic thymidine-based proliferation assays or sophisticated new cytometry assays, each assay has its relative advantages and disadvantages, and relatively few of these assays have yet to be validated in large-scale human vaccine trials. This review examines the current range of T-cell assays and assesses their suitability for use in human vaccine trials. Should one or more of these assays be accepted as an agreed surrogate of T-cell protection by a regulatory agency, this would significantly accelerate the development of T-cell vaccines.

Saade, Fadi; Gorski, Stacey Ann; Petrovsky, Nikolai

2013-01-01

298

CD4+CD25+Foxp3+ Regulatory T Cells Depletion May Attenuate the Development of Silica-Induced Lung Fibrosis in Mice  

Microsoft Academic Search

BackgroundSilicosis is an occupational lung disease caused by inhalation of silica dust characterized by lung inflammation and fibrosis. Previous study showed that Th1 and Th2 cytokines are involved in silicosis, but Th1\\/Th2 polarization during the development of silicosis is still a matter of debate. Regulatory T cells (Treg cells) represent a crucial role in modulation of immune homeostasis by regulating

Fangwei Liu; Jie Liu; Dong Weng; Ying Chen; Laiyu Song; Qincheng He; Jie Chen; Derya Unutmaz

2010-01-01

299

LF 15-0195 treatment protects against central nervous system autoimmunity by favoring the development of Foxp3-expressing regulatory CD4 T cells.  

PubMed

Experimental autoimmune encephalomyelitis (EAE) is an instructive model for the human demyelinating disease multiple sclerosis. Lewis (LEW) rats immunized with myelin-basic protein (MBP) develop EAE characterized by a single episode of paralysis, from which they recover spontaneously and become refractory to a second induction of disease. LF 15-0195 is a novel molecule that has potent immunosuppressive effects in several immune-mediated pathological manifestations, including EAE. In the present study, we show that a 30-day course of LF 15-0195 treatment not only prevents MBP-immunized LEW rats from developing EAE but also preserves their refractory phase to reinduction of disease. This effect is Ag driven since it requires priming by the autoantigen during the drug administration. In contrast to other immunosuppressive drugs, short-term treatment with this drug induces a persistent tolerance with no rebound of EAE up to 4 mo after treatment withdrawal. This beneficial effect of LF 15-0195 on EAE does not result from the deletion of MBP-specific Vbeta8.2 encephalitogenic T cells. In contrast, this drug favors the differentiation of MBP-specific CD4 T cells into Foxp3-expressing regulatory T cells that, upon adoptive transfer in syngeneic recipients, prevent the development of actively induced EAE. Finally, we demonstrate that the tolerance induced by LF 15-0195 treatment is not dependent on the presence of TGF-beta. Together, these data demonstrate that short-term treatment with LF 15-0195 prevents MBP-immunized LEW rats from EAE by favoring the development of Foxp-3-expressing regulatory CD4 T cells. PMID:16393967

Duplan, Valérie; Beriou, Gaëlle; Heslan, Jean-Marie; Bruand, Corinne; Dutartre, Patrick; Mars, Lennart T; Liblau, Roland S; Cuturi, Maria-Cristina; Saoudi, Abdelhadi

2006-01-15

300

T cell repertoires and competitive exclusion.  

PubMed

Self-renewal is generally thought to play a major role in the maintenance of the T-cell repertoire. Here we develop a set of mathematical models for T-cell activation by peptides on antigen presenting cells (APCs). We show that competition between T cells is inherent to the processes involved in T cells binding APCs. We prove that for each dominant peptide only one T-cell clone can ultimately survive the competition. This is analogous to a classical result from theoretical ecology known as the principle of "competitive exclusion". These findings allow for three main results. First, competitive exclusion during an immune response to antigen implies that the clone(s) with the highest affinity for the dominant peptide(s) will outcompete all others. This allows for a form of "affinity selection". Second, the competition for binding antigen gives rise to regulation of T-cell numbers within a single clone. This allows for a regulated form of T-cell memory when T cells are continuously activated by a persisting antigen. Third, competitive exclusion implies that for each peptide only one T-cell specificity can be maintained in the repertoire. If the T-cell repertoire is largely maintained owing to cross-reactivities with various antigens, competitive exclusion means that the diversity of the T-cell repertoire is limited by the number of antigens stimulating the system. If the cross-reactivities were to involve activation by self antigens this would confirm an earlier result suggesting that the T-cell repertoire is diverse owing to the diversity of the self environment. PMID:7967629

De Boer, R J; Perelson, A S

1994-08-21

301

Bovine ?? T Cells Are a Major Regulatory T Cell Subset.  

PubMed

In humans and mice, ?? T cells represent <5% of the total circulating lymphocytes. In contrast, the ?? T cell compartment in ruminants accounts for 15-60% of the total circulating mononuclear lymphocytes. Despite the existence of CD4(+)CD25(high) Foxp3(+) T cells in the bovine system, these are neither anergic nor suppressive. We present evidence showing that bovine ?? T cells are the major regulatory T cell subset in peripheral blood. These ?? T cells spontaneously secrete IL-10 and proliferate in response to IL-10, TGF-?, and contact with APCs. IL-10-expressing ?? T cells inhibit Ag-specific and nonspecific proliferation of CD4(+) and CD8(+) T cells in vitro. APC subsets expressing IL-10 and TFG-? regulate proliferation of ?? T cells producing IL-10. We propose that ?? T cells are a major regulatory T cell population in the bovine system. PMID:24890724

Guzman, Efrain; Hope, Jayne; Taylor, Geraldine; Smith, Adrian L; Cubillos-Zapata, Carolina; Charleston, Bryan

2014-07-01

302

Bovine ?? T cells are a major regulatory T cell subset  

PubMed Central

In humans and mice, ?? T cells represent less than 5% of the total circulating lymphocytes. In contrast, the ?? T cell compartment in ruminants accounts for 15-60% of the total circulating mononuclear lymphocytes. Despite the existence of CD4+CD25high Foxp3+ T cells in the bovine system, these are neither anergic nor suppressive. We now present evidence showing that bovine ?? T cells are the major regulatory T cell subset in peripheral blood. These ?? T cells spontaneously secrete IL-10 and proliferate in response to IL-10, TGF-? and contact with antigen presenting cells (APC). IL-10-expressing ?? T cells inhibit antigen-specific and non-specific proliferation of CD4+ and CD8+ T cells in vitro. APC subsets expressing IL-10 and TFG-? regulate proliferation of ?? T cells producing IL-10. We propose that ?? T cells are a major regulatory T cell population in the bovine system.

Guzman, Efrain; Hope, Jayne; Taylor, Geraldine; Smith, Adrian L.; Cubillos-Zapata, Carolina; Charleston, Bryan

2014-01-01

303

CD8+ Effector T Cells at the Fetal-Maternal Interface, Balancing Fetal Tolerance and Antiviral Immunity  

PubMed Central

During pregnancy CD8+ effector T cells need optimal immune regulation to prevent a detrimental response to allogeneic fetal cells while providing immune protection to infections. A significant proportion of (prospective) mothers carry naïve or memory CD8+ T cells with a TCR that can directly bind to paternal MHC molecules. In addition, a high percentage of pregnant women develop specific T cell responses to fetal minor histocompatibility antigens (mHags). Under normal conditions, fetal–maternal MHC and mHag mismatches lead to elevated lymphocyte activation but do not induce pregnancy failure. Furthermore, viral infections alter the maternal CD8+ T cell response by changing the CD8+ T cell repertoire and increasing the influx of CD8+ T cells to decidual tissue. The normally high T cell activation threshold at the fetal–maternal interface may prevent efficient clearance of viral infections. Conversely, the increased inflammatory response due to viral infections may break fetal–maternal tolerance and lead to pregnancy complications. The aim of this review is to discuss the recent studies of CD8+ T cells in pregnancy, identify potential mechanisms for antigen-specific immune recognition of fetal extravillous trophoblast (EVT) cells by CD8+ T cells, and discuss the impact of viral infections and virus-specific CD8+ T cells during pregnancy.

Tilburgs, Tamara; Strominger, Jack L.

2013-01-01

304

The N-methyl-d-aspartic acid receptor antagonist memantine ameliorates and delays the development of arthritis by enhancing regulatory T cells.  

PubMed

The neuroendocrine impact on rheumatoid arthritis is not yet fully described although numerous neurotransmitters are shown to act as inflammatory modulators. One of these is the excitatory transmitter glutamate (Glu). In this study, the influence of the Glu receptor (GluR)-mediated effects on collagen-induced arthritis (CIA) was investigated. CIA was induced in DBA/1 mice by immunization with chicken collagen type II (CII). Mice were exposed to the following GluR antagonists: group 1, the N-methyl-D-aspartic acid (NMDA) receptor channel blocker memantine; group 2, the metabotropic GluR antagonist AIDA, and group 3, the excitatory amino acid receptor antagonist kynurenic acid (KA). Arthritis was evaluated clinically and histologically and compared to PBS-treated controls. The effects of treatment on T cell populations and the levels of anti-CII and anti-citrullinated peptide antibodies were evaluated. Memantine treatment significantly improved the course of CIA, reducing synovitis (p = 0.007) and the frequency of erosions (p = 0.007). Memantine treatment up-regulated the expression of Foxp3 in spleen CD4+ T cells followed by an increase in CD4+CD25+ regulatory T cells. The other GluR antagonists, AIDA and KA, had no effect on CIA. These results demonstrate that blockade of the NMDA receptor channel with memantine delays and attenuates the development of arthritis, probably by promoting the development of regulatory T lymphocytes. PMID:22134197

Lindblad, Sofia S; Mydel, Piotr; Hellvard, Annelie; Jonsson, Ing-Marie; Bokarewa, Maria I

2012-01-01

305

Itm2a, a Target Gene of GATA-3, Plays a Minimal Role in Regulating the Development and Function of T Cells.  

PubMed

The integral membrane protein 2a (Itm2a) is one of the BRICHOS domain-containing proteins and is structurally related to Itm2b and Itm2c. It is expressed preferentially in the T lineage among hematopoietic cells and is induced by MHC-mediated positive selection. However, its transcriptional regulation and function are poorly understood. Here we showed Itm2a to be a target gene of GATA-3, a T cell-specific transcription factor. Deficiency of Itm2a had little impact on the development and function of polyclonal T cells but resulted in a partial defect in the development of thymocytes bearing a MHC class I-restricted TCR, OT-I. In addition, Itm2a-deficient mice displayed an attenuated T helper cell-dependent immune response in vivo. We further demonstrated that Itm2b but not Itm2c was also expressed in T cells, and was induced upon activation, albeit following a kinetic different from that of Itm2a. Thus, functional redundancy between Itm2a and Itm2b may explain the minimal phenotype of Itm2a deficiency. PMID:24831988

Tai, Tzong-Shyuan; Pai, Sung-Yun; Ho, I-Cheng

2014-01-01

306

IL-23 from langerhans cells is required for the development of imiquimod-induced psoriasis-like dermatitis by induction of IL-17A-producing ?? T cells.  

PubMed

Psoriasis is a common chronic inflammatory skin disease that involves dysregulated interplay between immune cells and keratinocytes. Recently, it has been reported that IL-23 induces CCR6+ ?? T cells, which have the pivotal role in psoriasis-like skin inflammation in mice of producing IL-17A and IL-22. Langerhans cells (LCs) are a subset of dendritic cells that reside in the epidermis and regulate immune responses. The role of LCs has been extensively investigated in contact hypersensitivity, but their role in psoriasis remains to be clarified. In this study, we focused on Th17-related factors and assessed the role of LCs and ?? T cells in the development of psoriasis using a mouse psoriasis model triggered by topical application of imiquimod (IMQ). LC depletion by means of diphtheria toxin (DT) in Langerin DT receptor-knocked-in mice suppressed hyperkeratosis, parakeratosis, and ear swelling in the IMQ-treated regions. In addition, LC-depleted mice showed decreased levels of Th17-related cytokines in IMQ-treated skin lesions. Moreover, the IMQ-treated skin of LC-depleted mice showed a decreased number of IL-17A-producing CCR6+ ?? T cells. These results suggest that LCs are required for the development of psoriasis-like lesions induced by IMQ in mice. PMID:24569709

Yoshiki, Ryutaro; Kabashima, Kenji; Honda, Tetsuya; Nakamizo, Satoshi; Sawada, Yu; Sugita, Kazunari; Yoshioka, Haruna; Ohmori, Shun; Malissen, Bernard; Tokura, Yoshiki; Nakamura, Motonobu

2014-07-01

307

Itm2a, a Target Gene of GATA-3, Plays a Minimal Role in Regulating the Development and Function of T Cells  

PubMed Central

The integral membrane protein 2a (Itm2a) is one of the BRICHOS domain-containing proteins and is structurally related to Itm2b and Itm2c. It is expressed preferentially in the T lineage among hematopoietic cells and is induced by MHC-mediated positive selection. However, its transcriptional regulation and function are poorly understood. Here we showed Itm2a to be a target gene of GATA-3, a T cell-specific transcription factor. Deficiency of Itm2a had little impact on the development and function of polyclonal T cells but resulted in a partial defect in the development of thymocytes bearing a MHC class I-restricted TCR, OT-I. In addition, Itm2a-deficient mice displayed an attenuated T helper cell-dependent immune response in vivo. We further demonstrated that Itm2b but not Itm2c was also expressed in T cells, and was induced upon activation, albeit following a kinetic different from that of Itm2a. Thus, functional redundancy between Itm2a and Itm2b may explain the minimal phenotype of Itm2a deficiency.

Tai, Tzong-Shyuan; Pai, Sung-Yun; Ho, I-Cheng

2014-01-01

308

Transiently reduced PI3K/Akt activity drives the development of regulatory function in antigen-stimulated Naïve T-cells.  

PubMed

Regulatory T-cells (Tregs) are central for immune homeostasis and divided in thymus-derived natural Tregs and peripherally induced iTreg. However, while phenotype and function of iTregs are well known, a remarkable lack exists in knowledge about signaling mechanisms leading to their generation from naïve precursors in peripheral tissues. Using antigen specific naïve T-cells from mice, we investigated CD4+ CD25+ FoxP3- iTreg induction during antigen-specific T-cell receptor (TCR) stimulation with weak antigen presenting cells (APC). We show that early signaling pathways such as ADAM-17-activation appeared similar in developing iTreg and effector cells (Teff) and both initially shedded CD62-L. But iTreg started reexpressing CD62-L after 24 h while Teff permanently downmodulated it. Furthermore, between 24 and 72 hours iTreg presented with significantly lower phosphorylation levels of Akt-S473 suggesting lower activity of the PI3K/Akt-axis. This was associated with a higher expression of the Akt hydrophobic motif-specific phosphatase PHLPP1 in iTreg. Importantly, the lack of costimulatory signals via CD28 from weak APC was central for the development of regulatory function in iTreg but not for the reappearance of CD62-L. Thus, T-cells display a window of sensitivity after onset of TCR triggering within which the intensity of the PI3K/Akt signal controls entry into either effector or regulatory pathways. PMID:23874604

Etemire, Eloho; Krull, Marco; Hasenberg, Mike; Reichardt, Peter; Gunzer, Matthias

2013-01-01

309

Impaired autophagy, defective T cell homeostasis and a wasting syndrome in mice with a T cell-specific deletion of Vps34  

PubMed Central

Autophagy plays a critical role in multiple aspects of the immune system, including the development and function of T lymphocytes. In mammalian cells, the class III phosphoinositide 3-kinase Vps34 is thought to play a critical role in autophagy. However, recent studies have cast doubt on the role of Vps34 in autophagy, at least in certain cell types. In order to study the effects of Vps34 on autophagy in T lymphocytes, we generated mice that selectively lack Vps34 in the T cell lineage. Vps34 ablation in T cells caused profound defects in autophagic flux, resulting in accumulation of cellular organelles and apoptosis. These animals exhibited normal intrathymic development of conventional T cells, but were profoundly impaired in the intrathymic development of invariant natural killer T cells. In peripheral organs, T cell-specific ablation of Vps34 had a profound impact on T cell homeostasis and function. Furthermore, aged animals developed an inflammatory wasting syndrome characterized by weight loss, intestinal inflammation and anemia. Consistent with this phenotype, Vps34 was required for the peripheral maintenance and function of CD4+FoxP3+ regulatory T cells. Collectively, our study reveals a critical role for Vps34 in autophagy and for the peripheral homeostasis and function of T lymphocytes.

Parekh, Vrajesh V.; Wu, Lan; Boyd, Kelli L.; Williams, Janice A.; Gaddy, Jennifer A.; Olivares-Villagomez, Danyvid; Cover, Timothy L.; Zong, Wei-Xing; Zhang, Jianhua; Van Kaer, Luc

2013-01-01

310

Deficient contact hypersensitivity reaction in CD4-/- mice is because of impaired hapten-specific CD8+ T cell functions.  

PubMed

Mice deficient in the CD4 molecule (CD4-/-) are widely used to evaluate the requirement for CD4+ T cell help in viral, tumoral, and transplantation immunity. Previous studies, showing that CD4-/- mice develop impaired contact hypersensitivity (CHS) responses, have suggested that CD4+ T cells are required for the optimal induction of this skin inflammatory reaction. other studies have, however, demonstrated that CHS was mediated by CD8+ T cells, without the need for CD4+ T cell help. Here, we show that CD4-/- mice develop a normal delayed-type hypersensitivity response to protein antigen, which is mediated by major histocompatibility molecules class II-restricted CD4-CD8- T cells, but a decreased CHS response to 2,4-dinitro-fluorobenezene. Analysis of the hapten-specific T cell pool demonstrates that priming of CD8+ T cells occurred normally in CD4-/- mice, as assessed by specific proliferative responses and interferon-gamma (IFN-gamma) production of purified CD8+ T cells. Furthermore, CD8+ T cells were able to adoptively transfer a normal CHS reaction. In contrast, total lymph node cells from CD4-/- mice showed decreased IFN-gamma production and diminished specific cytotoxic T lymphocytes (CTL) activity, which could be reversed by in vitro restimulation with hapten-pulsed class II-deficient antigen-presenting cells. These data confirm that class I-restricted CD8+ T cells can fully develop in effectors of CHS in the absence of CD4+ T cell help and suggest that the impaired CHS in CD4-/- mice is because of the presence of a class II-restricted T cell subset, which controls CHS by inhibiting hapten-specific CTL responses. PMID:15737197

Saint-Mezard, Pierre; Chavagnac, Cyril; Vocanson, Marc; Kehren, Jeanne; Rozières, Aurore; Bosset, Sophie; Ionescu, Marius; Dubois, Bertrand; Kaiserlian, Dominique; Nicolas, Jean-Francois; Bérard, Frédéric

2005-03-01

311

The graft-versus-host reaction and immune function. III. Functional pre-T cells in the bone marrow of graft-versus-host-reactive mice displaying T cell immunodeficiency.  

PubMed

Studies were performed to determine whether pre-T cells develop normally in the bone marrow of mice displaying thymic dysplasia and T cell immunodeficiency as a consequence of a graft-versus-host (GVH) reaction. GVH reactions were induced in CBAxAF1 mice by the injection of A strain lymphoid cells. To test for the presence of pre-T cells in GVH-reactive mice, bone marrow from GVH-reactive mice (GVHBM) was injected into irradiated syngeneic F1 mice and 30-40 days later thymic morphology and function were studied. Morphology studies showed nearly normal thymic architectural restoration; moreover, such glands contained normal numbers of Thy-1-positive cells. Functional pre-T cells were evaluated by transferring thymocytes from the irradiated GVHBM-reconstituted mice into T-cell-deprived mice. These thymocytes reconstituted allograft reactivity, T helper cell function and Con A and PHA mitogen responses of T-cell-deprived mice. These results suggest that the pre-T cell population in the bone marrow is not affected by the GVH reaction. Therefore, the T cell immunodeficiency associated with the GVH reaction is not due to a deficiency of pre-T cells in the bone marrow but is more likely associated with GVH-induced thymic dysplasia. PMID:3484849

Seddik, M; Seemayer, T A; Lapp, W S

1986-02-01

312

Impaired T Cell Death and Lupus-like Autoimmunity in T Cell-specific Adapter Protein-deficient Mice  

PubMed Central

T cell–specific adaptor protein (TSAd) is a T lineage–restricted signaling adaptor molecule that is thought to participate in the assembly of intracellular signaling complexes in T cells. Previous studies of TSAd-deficient mice have revealed a role for TSAd in the induction of T cell interleukin 2 secretion and proliferation. We now show that TSAd-deficient mice are susceptible to lupus-like autoimmune disease. On the nonautoimmune-prone C57BL/6 genetic background, TSAd deficiency results in hypergammaglobulinemia that affects all immunoglobulin (Ig)G subclasses. Older C57BL/6 TSAd-deficient mice (1 yr of age) accumulate large numbers of activated T and B cells in spleen, produce autoantibodies against a variety of self-targets including single stranded (ss) and double stranded (ds) DNA, and, in addition, develop glomerulonephritis. We further show that immunization of younger C57BL/6 TSAd-deficient mice (at age 2 mo) with pristane, a recognized nonspecific inflammatory trigger of lupus, results in more severe glomerulonephritis compared with C57BL/6 controls and the production of high titer ss and ds DNA antibodies of the IgG subclass that are not normally produced by C57BL/6 mice in this model. The development of autoimmunity in TSAd-deficient mice is associated with defective T cell death in vivo. These findings illustrate the role of TSAd as a critical regulator of T cell death whose absence promotes systemic autoimmunity.

Drappa, Jorn; Kamen, Lynn A.; Chan, Elena; Georgiev, Maria; Ashany, Dalit; Marti, Francesc; King, Philip D.

2003-01-01

313

Antigen-Induced Pten Gene Deletion in T Cells Exacerbates Neuropathology in Experimental Autoimmune Encephalomyelitis  

PubMed Central

The Pten tumor suppressor gene is critical for normal intrathymic development of T cells; however, its role in mature antigen-activated T cells is less well defined. A genetically crossed mouse line, Ptenfl/fl GBC, in which Pten gene deletions could be primarily confined to antigen-activated CD8+ T cells, enabled us to evaluate the consequences of Pten loss on the course of experimental autoimmune encephalomyelitis. Compared with Ptenfl/fl controls, myelin oligodendrocyte glycoprotein (MOG) peptide-immunized Ptenfl/fl GBC mice developed more severe and protracted disease. This was accompanied by increased spinal cord white matter myelin basic protein depletion and axonal damage, as well as a striking persistence of macrophage and granzyme B-expressing cellular neuroinfiltrates in the chronic phase of the disease. This persistence may be explained by the observation that anti-CD3 activated Ptenfl/fl GBC T cells were more resistant to proapoptotic stimuli. Consistent with the predicted consequences of Pten loss, purified CD8+ T cells from Ptenfl/fl GBC mice displayed augmented proliferative responses to anti-T-cell receptor stimulation, and MOG-primed Ptenfl/fl GBC T cells exhibited a reduced activation threshold to MOG peptide. Ptenfl/fl GBC mice also developed atypical central nervous system disease, manifested by prominent cervical cord and forebrain involvement. Collectively, our findings indicate that the phosphatidylinositol 3-kinase signaling pathway is an essential regulator of CD8+ T-cell effector function in experimental autoimmune encephalomyelitis.

Johnson, Trina A.; Tsutsui, Shigeki; Jirik, Frank R.

2008-01-01

314

Selectively Reduced Intracellular Proliferation of Salmonella enterica Serovar Typhimurium within APCs Limits Antigen Presentation and Development of a Rapid CD8 T Cell Response1  

PubMed Central

Ag presentation to CD8+ T cells commences immediately after infection, which facilitates their rapid expansion and control of pathogen. This paradigm is not followed during infection with virulent Salmonella enterica serovar Typhimurium (ST), an intracellular bacterium that causes mortality in susceptible C57BL/6J mice within 7 days and a chronic infection in resistant mice (129 × 1SvJ). Infection of mice with OVA-expressing ST results in the development of a CD8+ T cell response that is detectable only after the second week of infection despite the early detectable bacterial burden. The mechanism behind the delayed CD8+ T cell activation was evaluated, and it was found that dendritic cells/macrophages or mice infected with ST-OVA failed to present Ag to OVA-specific CD8+ T cells. Lack of early Ag presentation was not rescued when mice or dendritic cells/macrophages were infected with an attenuated aroA mutant of ST or with mutants having defective Salmonella pathogenicity island I/II genes. Although extracellular ST proliferated extensively, the replication of ST was highly muted once inside macrophages. This muted intracellular proliferation of ST resulted in the generation of poor levels of intracellular Ag and peptide-MHC complex on the surface of dendritic cells. Additional experiments revealed that ST did not actively inhibit Ag presentation, rather it inhibited the uptake of another intracellular pathogen, Listeria monocytogenes, thereby causing inhibition of Ag presentation against L. monocytogenes. Taken together, this study reveals a dichotomy in the proliferation of ST and indicates that selectively reduced intra-cellular proliferation of virulent pathogens may be an important mechanism of immune evasion.

Albaghdadi, Homam; Robinson, Nirmal; Finlay, Brett; Krishnan, Lakshmi; Sad, Subash

2014-01-01

315

SJL Mice Infected with Acanthamoeba castellanii Develop Central Nervous System Autoimmunity through the Generation of Cross-Reactive T Cells for Myelin Antigens  

PubMed Central

We recently reported that Acanthamoeba castellanii (ACA), an opportunistic pathogen of the central nervous system (CNS) possesses mimicry epitopes for proteolipid protein (PLP) 139–151 and myelin basic protein 89–101, and that the epitopes induce experimental autoimmune encephalomyelitis (EAE) in SJL mice reminiscent of the diseases induced with their corresponding cognate peptides. We now demonstrate that mice infected with ACA also show the generation of cross-reactive T cells, predominantly for PLP 139–151, as evaluated by T cell proliferation and IAs/dextramer staining. We verified that PLP 139–151-sensitized lymphocytes generated in infected mice contained a high proportion of T helper 1 cytokine-producing cells, and they can transfer disease to naïve animals. Likewise, the animals first primed with suboptimal dose of PLP 139–151 and later infected with ACA, developed EAE, suggesting that ACA infection can trigger CNS autoimmunity in the presence of preexisting repertoire of autoreactive T cells. Taken together, the data provide novel insights into the pathogenesis of Acanthamoeba infections, and the potential role of infectious agents with mimicry epitopes to self-antigens in the pathogenesis of CNS diseases such as multiple sclerosis.

Massilamany, Chandirasegaran; Marciano-Cabral, Francine; da Rocha-Azevedo, Bruno; Jamerson, Melissa; Gangaplara, Arunakumar; Steffen, David; Zabad, Rana; Illes, Zsolt; Sobel, Raymond A.; Reddy, Jay

2014-01-01

316

CD4+ T Cell-Depleted Lymphocyte Infusion Impairs Neither the Recovery of Recipient Thymus nor the Development of Transplanted Thymus  

PubMed Central

Thymus transplantation, in conjunction with bone marrow transplantation (BMT), has been attracting attention for the treatment of various diseases. Recently, donor lymphocyte infusion (DLI) has been used as a helpful tool for establishing donor chimerism and preventing a relapse of leukemia/lymphoma. However, the effects of DLI on transplanted and recipient thymuses have not been explored. We therefore performed DLI in the intrabone marrow–BMT + thymus transplantation setting. We have found that DLI leads to derangements in both recipient thymuses and transplanted thymuses; by 2 wk after BMT, we saw a decrease in total cell number, a lower percentage of CD4+CD8+ cells, and the obliteration of the thymic corticomedullary junction. Four weeks later, the thymic impairment became more serious. However, when we depleted the CD4+ T cells (CD4?-DLI), the recipient thymic recovery and transplanted thymic development were significantly restored by the treatment. In addition, there were much greater levels of TNF-? and Fas ligand, and a lower percentage of regulatory T cells in the DLI group than in the CD4?-DLI group. These findings indicate that inflammation induced by DLI, especially by CD4+ T cells, plays a crucial role in the thymic impairment.

Shi, Ming; Li, Ming; Cui, Yunze; Liu, Lin; Adachi, Yasushi

2013-01-01

317

Prenatal exposure to radiofrequencies: effects of WiFi signals on thymocyte development and peripheral T cell compartment in an animal model.  

PubMed

Wireless local area networks are an increasing alternative to wired data networks in workplaces, homes, and public areas. Concerns about possible health effects of this type of signal, especially when exposure occurs early in life, have been raised. We examined the effects of prenatal (in utero) exposure to wireless fidelity (WiFi) signal-associated electromagnetic fields (2450?MHz center-frequency band) on T cell development and function. Pregnant mice were exposed whole body to a specific absorption rate of 4?W/kg, 2?h per day, starting 5 days after mating and ending 1 day before the expected delivery. Sham-exposed and cage control groups were used as controls. No effects on cell count, phenotype, and proliferation of thymocytes were observed. Also, spleen cell count, CD4/CD8 cell frequencies, T cell proliferation, and cytokine production were not affected by the exposure. These findings were consistently observed in the male and female offspring at early (5 weeks of age) and late (26 weeks of age) time points. Nevertheless, the expected differences associated with aging and/or gender were confirmed. In conclusion, our results do not support the hypothesis that the exposure to WiFi signals during prenatal life results in detrimental effects on the immune T cell compartment. PMID:22556007

Laudisi, Federica; Sambucci, Manolo; Nasta, Francesca; Pinto, Rosanna; Lodato, Rossella; Altavista, Pierluigi; Lovisolo, Giorgio Alfonso; Marino, Carmela; Pioli, Claudio

2012-12-01

318

Progesterone suppresses Th17 cell responses, and enhances the development of regulatory T cells, through thymic stromal lymphopoietin-dependent mechanisms in experimental gonococcal genital tract infection.  

PubMed

In most female patients, the symptoms of genital infection due to Neisseria gonorrhoeae tend to be slight or even absent. Our previous studies suggested that progesterone might play a role in female asymptomatic gonococcal infection. In this study, we demonstrated that progesterone induced the expression of thymic stromal lymphopoietin (TSLP) and regulatory T cells (Treg)-related transcription factor Foxp3, and inhibited the expression of Th17 related transcription factor ROR?t, and reduced the influx of neutrophils in murine vaginal gonococcal infection. Blockade of TSLP with antibody partially reversed the effects of progesterone on the murine model of gonococcal vaginal infection. In in vitro experiments, progesterone induced a rapid up-regulation of TSLP in vaginal epithelial cells stimulated with N. gonorrhoeae. Blocking thymic stromal lymphopoietin receptor (TSLPR) with a TSLPR monoclonal antibody partially prevented progesterone suppression of IL-17-producing T cells differentiation, and progesterone promotion of CD4?CD25?Foxp3? regulatory T cells differentiation. Altogether, our results indicate that the progesterone suppresses Th17 cell responses, and enhances the development of Treg cells, through TSLP-dependent mechanisms, and play a role in female asymptomatic gonococcal infections. PMID:23835188

Xu, Li; Dong, Bilin; Wang, Hui; Zeng, Zhiliang; Liu, Weihuang; Chen, Na; Chen, Jinbo; Yang, Jing; Li, Dongsheng; Duan, Yiqun

2013-11-01

319

A Th1 cytokine-enriched microenvironment enhances tumor killing by activated T cells armed with bispecific antibodies and inhibits the development of myeloid-derived suppressor cells  

PubMed Central

In this study, we investigated whether activated T cells (ATC) armed with bispecific antibodies (aATC) can inhibits tumor growth and MDSC development in a Th1 cytokine–enriched (IL-2 and IFN-?) microenvironment. Cytotoxicity mediated by aATC was significantly higher (P <0.001) against breast cancer cell lines in the presence of Th1 cytokines as compared with control co-cultures. In the presence of aATC, CD33+/CD11b+/CD14?/HLA-DR?MDSC population was reduced significantly under both control (P <0.03) and Th1-enriched (P <0.036) culture conditions. Cytokine analysis in the culture supernatants showed high levels of MDSC suppressive chemokines CXCL9 and CXCL10 in Th1-enriched culture supernatants with highly significant increase (P <0.001) in the presence of aATC. Interestingly, MDSC recovered from co-cultures without aATC showed potent ability to suppress activated T-cell-mediated cytotoxicity (P <0.001), IFN-? production (P <0.01) and T-cell proliferation (P <0.05) compared to those recovered from aATC-containing co-cultures. These data suggest that aATC can mediate enhanced killing of tumor cells and may suppress MDSC and Treg differentiation, and presence of Th1 cytokines potentiates aATC-induced suppression of MDSC, sug-gesting that Th1-enriching immunotherapy may be benefi-cial in cancer treatment.

Schalk, Dana; Sarkar, Sanila H.; Al-Khadimi, Zaid; Sarkar, Fazlul H.; Lum, Lawrence G.

2013-01-01

320

A Th1 cytokine-enriched microenvironment enhances tumor killing by activated T cells armed with bispecific antibodies and inhibits the development of myeloid-derived suppressor cells.  

PubMed

In this study, we investigated whether activated T cells (ATC) armed with bispecific antibodies (aATC) can inhibits tumor growth and MDSC development in a Th1 cytokine-enriched (IL-2 and IFN-?) microenvironment. Cytotoxicity mediated by aATC was significantly higher (P < 0.001) against breast cancer cell lines in the presence of Th1 cytokines as compared with control co-cultures. In the presence of aATC, CD33+ /CD11b+ /CD14- /HLA-DR- MDSC population was reduced significantly under both control (P < 0.03) and Th1-enriched (P < 0.036) culture conditions. Cytokine analysis in the culture supernatants showed high levels of MDSC suppressive chemokines CXCL9 and CXCL10 in Th1-enriched culture supernatants with highly significant increase (P < 0.001) in the presence of aATC. Interestingly, MDSC recovered from co-cultures without aATC showed potent ability to suppress activated T-cell-mediated cytotoxicity (P < 0.001), IFN-? production (P < 0.01) and T-cell proliferation (P < 0.05) compared to those recovered from aATC-containing co-cultures. These data suggest that aATC can mediate enhanced killing of tumor cells and may suppress MDSC and T(reg) differentiation, and presence of Th() cytokines potentiates aATC-induced suppression of MDSC, suggesting that Th1-enriching immunotherapy may be beneficial in cancer treatment. PMID:21971587

Thakur, Archana; Schalk, Dana; Sarkar, Sanila H; Al-Khadimi, Zaid; Sarkar, Fazlul H; Lum, Lawrence G

2012-04-01

321

Development of angioimmunoblastic T-cell lymphoma after treatment of diffuse large B-cell lymphoma: a case report and review of literature  

PubMed Central

Cases of diffuse large B-cell lymphoma (DLBCL) arising after the initial diagnosis of angioimmunoblastic T-cell lymphoma (AITL) and DLBCL synchronous with AITL have been reported. To date, there is no report on the subsequent development of AITL in patients with DLBCL. Here we presented a rare case of AITL developing six months after the initial diagnosis of DLBCL. In order to investigate the clinical and molecular features of patients with AITL and DLBCL, we also reviewed the literature on AITL patients developing DLBCL, and patients with composite AITL and DLBCL.

Wang, Yaya; Xie, Bailu; Chen, Yu; Huang, Zhenqian; Tan, Huo

2014-01-01

322

Signal Transduction via the T cell Antigen Receptor in na?ve and effector/memory T cells  

PubMed Central

T cells play an indispensable role in immune defense against infectious agents, but can also be pathogenic. These T cells develop in the thymus, are exported into the periphery as naïve cells and participate in immune responses. Upon recognition of antigen, they are activated and differentiate into effector and memory T cells. While effector T cells carry out the function of the immune response, memory T cells can last up to the life time of the individual, and are activated by subsequent antigenic exposure. Throughout this life cycle, the T cell uses the same receptor for antigen, the T cell Receptor, a complex multi-subunit receptor. Recognition of antigen presented by peptide/MHC complexes on antigen presenting cells unleashes signaling pathways that control T cell activation at each stage. In this review, we discuss the signals regulated by the T cell receptor in naïve and effector/memory T cells.

Kannan, Arun; Huang, Weishan; Huang, Fei; August, Avery

2012-01-01

323

N'-methylnicotinamide blocks activation of normal and leukemic T cell line at an early stage of the cell cycle; role of ADP-ribosylation in the transcription of IL-2  

SciTech Connect

The authors analyzed the role of ADP-ribosyl transferase (ADPRT) in the mitogen induced activation of normal peripheral blood lymphocytes and leukemic T cell line Jurkats through the use of an ADPRT inhibitor. Addition of N'-methylnicotinamide (N'-MN) in the range of 1-10 mM reduced IL-2 production and IL-2 receptor (TAC) expression in both cell specimens in a dose dependent fashion when added before or at the same time as ConA, PHA (+ TPA in Jurkats). When N'-MN was added at different times after mitogens, a sigmoid curve response was obtained. The drug was effective only when added in the early stages of activation (1st 8 hours), causing reduction of viability and cell cycle progression (blast formation-DNA synthesis) and expression of all activation markers such as TAC, OKT-9, OKT-10, and HLA-DR. Late addition of the drug (24 hours or later) had no effect. Exogenous recombinant IL-2 (15 units/ml) partially reversed the N'-MN induced inhibition of /sup 3/H-Thymidine incorporation into DNA from mitogen stimulated normal T cells. Northern blot analysis revealed that N'-MN blocks the transcription of DNA to mRNA coding for IL-2. These data indicate that transcription of the genes involved in immune activation requires ADP-ribosylation of nuclear proteins.

Salazar-Gonzalez, J.F.; Rezai, A.R.; Kermain-Arab, V.

1986-03-05

324

Normal Development of Brain Circuits  

Microsoft Academic Search

Spanning functions from the simplest reflex arc to complex cognitive processes, neural circuits have diverse functional roles. In the cerebral cortex, functional domains such as visual processing, attention, memory, and cognitive control rely on the development of distinct yet interconnected sets of anatomically distributed cortical and subcortical regions. The developmental organization of these circuits is a remarkably complex process that

Gregory Z Tau; Bradley S Peterson

2010-01-01

325

CD8+ T cells are effector cells of contact dermatitis to common skin allergens in mice.  

PubMed

Allergic contact dermatitis (ACD) to strong experimental haptens is mediated by specific CD8+ T cells. Here, we show that similar mechanisms occur for weak haptens, which comprise the vast majority of chemicals responsible for human ACD. We used a model of ACD, that is, the contact hypersensitivity reaction, to test for the allergenicity of three weak haptens involved in fragrance allergy. ACD to weak haptens could not be induced in normal mice. In contrast, mice acutely depleted in CD4+ T cells developed a typical ACD reaction to the three weak fragrance allergens that peaked 24 hours after challenge. Priming of CD8+ T cells was observed in draining lymph nodes 5 days after sensitization and development of ACD was associated with the infiltration of activated CD8+ T cells in the challenged skin. CD8+ T cells were effectors of the ACD reaction as in vivo treatment with depleting anti-CD8 mAbs abrogated the ACD responses and as purified CD8+ T cells could adoptively transfer ACD to naive recipients. In conclusion, our data demonstrate a dominant role of CD8+ T cells as initiators of ACD to weak haptens, and suggest that CD8+ T cells may represent potential targets for preventing or treating ACD. PMID:16456532

Vocanson, Marc; Hennino, Anca; Cluzel-Tailhardat, Magalie; Saint-Mezard, Pierre; Benetiere, Josette; Chavagnac, Cyril; Berard, Frederic; Kaiserlian, Dominique; Nicolas, Jean-François

2006-04-01

326

Normal Development of Brain Circuits  

PubMed Central

Spanning functions from the simplest reflex arc to complex cognitive processes, neural circuits have diverse functional roles. In the cerebral cortex, functional domains such as visual processing, attention, memory, and cognitive control rely on the development of distinct yet interconnected sets of anatomically distributed cortical and subcortical regions. The developmental organization of these circuits is a remarkably complex process that is influenced by genetic predispositions, environmental events, and neuroplastic responses to experiential demand that modulates connectivity and communication among neurons, within individual brain regions and circuits, and across neural pathways. Recent advances in neuroimaging and computational neurobiology, together with traditional investigational approaches such as histological studies and cellular and molecular biology, have been invaluable in improving our understanding of these developmental processes in humans in both health and illness. To contextualize the developmental origins of a wide array of neuropsychiatric illnesses, this review describes the development and maturation of neural circuits from the first synapse through critical periods of vulnerability and opportunity to the emergent capacity for cognitive and behavioral regulation, and finally the dynamic interplay across levels of circuit organization and developmental epochs.

Tau, Gregory Z; Peterson, Bradley S

2010-01-01

327

Utilizing the adjuvant properties of CD1d-dependent NK T cells in T cell-mediated immunotherapy  

PubMed Central

Activation of invariant CD1d-dependent NK T cells (iNKT cells) in vivo through administration of the glycolipid ligand ?-galactosylceramide (?-GalCer) or the sphingosine-truncated ?-GalCer analog OCH leads to CD40 signaling as well as the release of soluble molecules including type 1 and ? interferons that contribute to DC maturation. This process enhances T cell immunity to antigens presented by the DC. The adjuvant activity is further amplified if APCs are stimulated through Toll-like receptor 4, suggesting that iNKT cell signals can amplify maturation induced by microbial stimuli. The adjuvant activity of ?-GalCer enhances both priming and boosting of CD8+ T cells to coadministered peptide or protein antigens, including a peptide encoding the clinically relevant, HLA-A2–restricted epitope of the human tumor antigen NY-ESO-1. Importantly, ?-GalCer was used to induce CD8+ T cells to antigens delivered orally, despite the fact that this route of administration is normally associated with blunted responses. Only T cell responses induced in the presence of iNKT cell stimulation, whether by the i.v. or oral route, were capable of eradicating established tumors. Together these data highlight the therapeutic potential of iNKT cell ligands in vaccination strategies, particularly “heterologous prime-boost” strategies against tumors, and provide evidence that iNKT cell stimulation may be exploited in the development of oral vaccines.

Silk, Jonathan D.; Hermans, Ian F.; Gileadi, Uzi; Chong, Tsung Wen; Shepherd, Dawn; Salio, Mariolina; Mathew, Bini; Schmidt, Richard R.; Lunt, Sarah Jane; Williams, Kaye J.; Stratford, Ian J.; Harris, Adrian L.; Cerundolo, Vincenzo

2004-01-01

328

Early signaling defects in human T cells anergized by T cell presentation of autoantigen  

PubMed Central

Major histocompatibility complex class II-positive human T cell clones are nontraditional antigen-presenting cells (APCs) that are able to simultaneously present and respond to peptide or degraded antigen, but are unable to process intact protein. Although T cell presentation of peptide antigen resulted in a primary proliferative response, T cells that had been previously stimulated by T cells presenting antigen were completely unresponsive to antigen but not to interleukin 2 (IL-2). In contrast, peptide antigen presented by B cells or DR2+ L cell transfectants resulted in T cell activation and responsiveness to restimulation. The anergy induced by T cell presentation of peptide could not be prevented by the addition of either autologous or allogeneic B cells or B7+ DR2+ L cell transfectants, suggesting that the induction of anergy could occur in the presence of costimulation. T cell anergy was induced within 24 h of T cell presentation of antigen and was long lasting. Anergized T cells expressed normal levels of T cell receptor/CD3 but were defective in their ability to release [Ca2+]i to both alpha CD3 and APCs. Moreover, anergized T cells did not proliferate to alpha CD2 monoclonal antibodies or alpha CD3 plus phorbol myristate acetate (PMA), nor did they synthesize IL-2, IL-4, or interferon gamma mRNA in response to either peptide or peptide plus PMA. In contrast, ionomycin plus PMA induced both normal proliferative responses and synthesis of cytokine mRNA, suggesting that the signaling defect in anergized cells occurs before protein kinase C activation and [Ca2+]i release.

1992-01-01

329

Expression of the B7.1 costimulatory molecule on pancreatic beta cells abrogates the requirement for CD4 T cells in the development of type 1 diabetes.  

PubMed

Although HLA-DQ8 has been implicated as a key determinant of genetic susceptibility to human type 1 diabetes, spontaneous diabetes has been observed in HLA-DQ8 transgenic mice that lack expression of murine MHC class II molecules (mII(-/-)) only when the potent costimulatory molecule, B7.1, is transgenically expressed on pancreatic beta cells. To study the contribution of HLA-DQ8 to the development of diabetes in this model, we crossed RIP-B7.1mII(-/-) mice with a set of transgenic mouse lines that differed in their HLA-DQ8 expression patterns on APC subpopulations, in particular dendritic cells and cortical thymic epithelial cells. Surprisingly, we found that even in the absence of HLA-DQ8 and CD4 T cells, a substantial fraction of the RIP-B7.1mII(-/-) mice developed diabetes. This disease process was remarkable for not only showing insulitis, but also inflammatory destruction of the exocrine pancreas with diffusely up-regulated expression of MHC class I and ICAM-1 molecules. Expression of HLA-DQ8 markedly increased the kinetics and frequency of diabetes, with the most severe disease in the lines with the highest levels of HLA-DQ8 on cortical thymic epithelial cells and the largest numbers of CD4 T cells. However, the adoptive transfer of diabetes was not HLA-DQ8-dependent and disease could be rapidly induced with purified CD8 T cells alone. Expression of B7.1 in the target tissue can thus dramatically alter the cellular and molecular requirements for the development of autoimmunity. PMID:15240665

Havari, Evis; Lennon-Dumenil, Ana Maria; Klein, Ludger; Neely, Devon; Taylor, Jacqueline A; McInerney, Marcia F; Wucherpfennig, Kai W; Lipes, Myra A

2004-07-15

330

Increased Th17 and regulatory T cell responses in EBV-induced gene 3-deficient mice lead to marginally enhanced development of autoimmune encephalomyelitis.  

PubMed

EBV-induced gene 3 (EBI3)-encoded protein can form heterodimers with IL-27P28 and IL-12P35 to form IL-27 and IL-35. IL-27 and IL-35 may influence autoimmunity by inhibiting Th17 differentiation and facilitating the inhibitory roles of Foxp3(+) regulatory T (Treg) cells, respectively. In this study, we have evaluated the development of experimental autoimmune encephalomyelitis (EAE) in EBI3-deficient mice that lack both IL-27 and IL-35. We found that myelin oligodendrocyte glycoprotein peptide immunization resulted in marginally enhanced EAE development in EBI3-deficient C57BL6 and 2D2 TCR-transgenic mice. EBI3 deficiency resulted in significantly increased Th17 and Th1 responses in the CNS and increased T cell production of IL-2 and IL-17 in the peripheral lymphoid organs. EBI3-deficient and -sufficient 2D2 T cells had equal ability in inducing EAE in Rag1(-/-) mice; however, more severe disease was induced in EBI3(-/-)Rag1(-/-) mice than in Rag1(-/-) mice by 2D2 T cells. EBI3-deficient mice had increased numbers of CD4(+)Foxp3(+) Treg cells in peripheral lymphoid organs. More strikingly, EBI3-deficient Treg cells had more potent suppressive functions in vitro and in vivo. Thus, our data support an inhibitory role for EBI3 in Th17, Th1, IL-2, and Treg responses. Although these observations are consistent with the known functions of IL-27, the IL-35 contribution to the suppressive functions of Treg cells is not evident in this model. Increased Treg responses in EBI3(-/-) mice may explain why the EAE development is only modestly enhanced compared with wild-type mice. PMID:22387555

Liu, Jin-Qing; Liu, Zhenzhen; Zhang, Xuejun; Shi, Yun; Talebian, Fatemeh; Carl, Joseph W; Yu, Chuan; Shi, Fu-Dong; Whitacre, Caroline C; Trgovcich, Joanne; Bai, Xue-Feng

2012-04-01

331

Cellular and molecular events in the localization of diabetogenic T cells to islets of Langerhans  

PubMed Central

Understanding the entry of autoreactive T cells to their target organ is important in autoimmunity because this entry initiates the inflammatory process. Here, the events that lead to specific localization of diabetogenic CD4 T cells into islets of Langerhans resulting in diabetes were examined. This was evaluated in two models, one in which T cells specific for a hen-egg white lysozyme (HEL) peptide were injected into mice expressing HEL on ? cells and the other using T cells in the nonobese diabetic mouse strain, which develops spontaneous diabetes. Only T cells specific for ?-cell antigens localized in islets within the first hours after their injection and were found adherent to intraislet dendritic cells (DCs). DCs surrounded blood vessels with dendrites reaching into the vessels. Localization of antigen-specific T cells did not require chemokine receptor signaling but involved class II histocompatibility and intercellular adhesion molecule 1 molecules. We found no evidence for nonspecific localization of CD4 T cells into normal noninflamed islets. Thus, the anatomy of the islet of Langerhans permits the specific localization of diabetogenic T cells at a time when there is no inflammation in the islets.

Calderon, Boris; Carrero, Javier A.; Miller, Mark J.; Unanue, Emil R.

2011-01-01

332

In situ recognition of autoantigen as an essential gatekeeper in autoimmune CD8+ T cell inflammation  

PubMed Central

A current paradigm states that non-antigen-specific inflammatory cues attract noncognate, bystander T cell specificities to sites of infection and autoimmune inflammation. Here we show that cues emanating from a tissue undergoing spontaneous autoimmune inflammation cannot recruit naive or activated bystander T cell specificities in the absence of local expression of cognate antigen. We monitored the recruitment of CD8+ T cells specific for the prevalent diabetogenic epitope islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)206–214 in gene-targeted nonobese diabetic (NOD) mice expressing a T cell “invisible” IGRP206–214 sequence. These mice developed islet inflammation and diabetes with normal incidence and kinetics, but their inflammatory lesions could recruit neither naive (endogenous or exogenous) nor ex vivo-activated IGRP206–214-reactive CD8+ T cells. Conversely, IGRP206–214-reactive, but not nonautoreactive CD8+ T cells rapidly homed to and accumulated in the inflamed islets of wild-type NOD mice. Our results indicate that CD8+ T cell recruitment to a site of autoimmune inflammation results from an active process that is strictly dependent on local display of cognate pMHC and suggest that CD8+ T cells contained in extralymphoid autoimmune lesions are largely autoreactive.

Wang, Jinguo; Tsai, Sue; Shameli, Afshin; Yamanouchi, Jun; Alkemade, Gonnie; Santamaria, Pere

2010-01-01

333

Improving the efficacy and safety of engineered T cell therapy for cancer.  

PubMed

Adoptive T-cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) is a powerful immunotherapeutics approach against metastatic melanoma. The success of TIL therapy has led to novel strategies for redirecting normal T cells to recognize tumor-associated antigens (TAAs) by genetically engineering tumor antigen-specific T cell receptors (TCRs) or chimeric antigen receptor (CAR) genes. In this manner, large numbers of antigen-specific T cells can be rapidly generated compared with the longer term expansion of TILs. Great efforts have been made to improve these approaches. Initial clinical studies have demonstrated that genetically engineered T cells can mediate tumor regression in vivo. In this review, we discuss the development of TCR and CAR gene-engineered T cells and the safety concerns surrounding the use of these T cells in patients. We highlight the importance of judicious selection of TAAs for modified T cell therapy and propose solutions for potential "on-target, off-organ" toxicity. PMID:23022475

Shi, Huan; Liu, Lin; Wang, Zhehai

2013-01-28

334

T cell vaccination therapy in an induced model of anti-RNP autoimmune glomerulonephritis.  

PubMed

To establish the relevance of targeting disease-associated T cells in anti-RNP-associated glomerulonephritis, mice developing nephritis following immunization with U1-70-kd small nuclear ribonucleoprotein (snRNP) were treated with a single dose of irradiated antigen-selected T cell vaccine. T cell receptor usage in nephritic kidneys revealed oligoclonal use of T Cell Receptor V Beta (TRBV) genes as previously found in spleens and lungs of immunized mice with pulmonary disease. The CDR3 regions from T cell isolates showed sequence homology to those in humans with anti-RNP autoimmunity. Following T cell vaccination, urinalysis returned to normal in 5/7 treated mice (71% response rate) whereas all mock-treated mice continued to have an active urinary sediment (Fisher's Exact p=0.02). An oligoclonal population of T cells homologous to those identified in humans with anti-RNP autoimmunity is implicated in disease pathogenesis, and T cell vaccination is associated with a high rate of clinical improvement in established nephritis. PMID:20797908

Trivedi, Sapna; Zang, YunJuan; Culpepper, Schartess; Rosenbaum, Erica; Fernandez, Irina; Martinez, Laisel; Hoffman, Robert W; Greidinger, Eric L

2010-11-01

335

Role of CD8(+) T-cell immunity in influenza infection: potential use in future vaccine development.  

PubMed

Continued circulation of the highly pathogenic avian H5N1 influenza A virus has many people worried that an influenza pandemic is imminent. Compounding this is the realization that H5N1 vaccines based on current influenza vaccine technology (designed to generate protective antibody responses) may be suboptimal at providing protection. As a consequence, there is recent interest in vaccine strategies that elicit cellular immunity, particularly the cytotoxic T lymphocyte response, in an effort to provide protection against a potential pandemic. A major issue is the lack of information about the precise role that these 'hitmen' of the immune system have in protecting against both pandemic and seasonal influenza. We need to know more about how the induction and maintenance of cytotoxic T lymphocytes after influenza infection can impact protection from further infection. The challenge is then to use this information in the design of vaccines that will protect against pandemic influenza and will help optimize CD8(+) killer T-cell responses in other infections. PMID:20477341

La Gruta, Nicole; Kelso, Anne; Brown, Lorena E; Chen, Wiesan; Jackson, David C; Turner, Stephen J

2009-10-01

336

Generation of colitogenic Th17 CD4 T cells is enhanced by IL-17+?? T cells  

PubMed Central

Th17 cells have been implicated in the pathogenesis of colitis; however, a cellular mechanism by which colitogenic Th17 immunity arises in vivo remains unclear. In this study, we report that a subset of IL-17+?? T cells plays a crucial role in enhancing in vivo Th17 differentiation and T cell-mediated colitis. TCR?-/- mice were highly susceptible to T cell-mediated colitis, while TCR??-/- mice were resistant to the disease. Importantly, cotransfer of IL-17+ but not of IL-17-?? T cells with CD4 T cells was sufficient to enhance Th17 differentiation and induce full-blown colitis in TCR??-/- recipients. Collectively, our results provide a novel function of IL-17+?? T cell subsets in supporting in vivo Th17 differentiation and possibly in fostering the development of intestinal inflammation.

Do, Jeong-su; Visperas, Anabelle; Dong, Chen; Baldwin, William M.; Min, Booki

2011-01-01

337

Genetically Modified T Cells for the Treatment of Malignant Disease  

PubMed Central

Summary The broaden application of adoptive T-cell transfer has been constrained by the technical abilities to isolate and expand antigen-specific T cells potent to selectively kill tumor cells. With the recent progress in the design and manufacturing of cellular products, T cells used in the treatment of malignant diseases may be regarded as anticancer biopharmaceuticals. Genetical manipulation of T cells has given T cells desired specificity but also enable to tailor their activation and proliferation potential. Here, we summarize the recent developments in genetic engineering of T-cell-based biopharmaceuticals, covering criteria for their clinical application in regard to safety and efficacy.

Wieczorek, Agnieszka; Uharek, Lutz

2013-01-01

338

Development and validation of TOF-SIMS and CLSM imaging method for cytotoxicity study of ZnO nanoparticles in HaCaT cells.  

PubMed

Zinc oxide nanoparticles (ZnO NPs) exhibit novel physiochemical properties and have found increasing use in sunscreen products and cosmetics. The potential toxicity is of increasing concern due to their close association with human skin. A time-of-flight secondary ion mass spectrometry (TOF-SIMS) and confocal laser scanning microscopy (CLSM) imaging method was developed and validated for rapid and sensitive cytotoxicity study of ZnO NPs using human skin equivalent HaCaT cells as a model system. Assorted material, chemical, and toxicological analysis methods were used to confirm their shape, size, crystalline structure, and aggregation properties as well as dissolution behavior and effect on HaCaT cell viability in the presence of various concentrations of ZnO NPs in aqueous media. Comparative and correlative analyses of aforementioned results with TOF-SIMS and CLSM imaging results exhibit reasonable and acceptable outcome. A marked drop in survival rate was observed with 50?g/ml ZnO NPs. The CLSM images reveal the absorption and localization of ZnO NPs in cytoplasm and nuclei. The TOF-SIMS images demonstrate elevated levels of intracellular ZnO concentration and associated Zn concentration-dependent (40)Ca/(39)K ratio, presumably caused by the dissolution behavior of ZnO NPs. Additional validation by using stable isotope-labeled (68)ZnO NPs as tracers under the same experimental conditions yields similar cytotoxicity effect. The imaging results demonstrate spatially-resolved cytotoxicity relationship between intracellular ZnO NPs, (40)Ca/(39)K ratio, phosphocholine fragments, and glutathione fragments. The trend of change in TOF-SIMS spectra and images of ZnO NPs treated HaCaT cells demonstrate the possible mode of actions by ZnO NP involves cell membrane disruption, cytotoxic response, and ROS mediated apoptosis. PMID:24731914

Lee, Pei-Ling; Chen, Bo-Chia; Gollavelli, Ganesh; Shen, Sin-Yu; Yin, Yu-Sheng; Lei, Shiu-Ling; Jhang, Cian-Ling; Lee, Woan-Ruoh; Ling, Yong-Chien

2014-07-30

339

Cutaneous T-cell Lymphomas  

Microsoft Academic Search

\\u000a T-cell malignancies presenting in the skin include mycosis fungoides, primary cutaneous anaplastic large cell lymphoma, and\\u000a the related regressing lesion lymphomatoid papulosis as well as viral-associated adult T-cell leukemia\\/lymphoma. Rarer and\\u000a more aggressive primary cutaneous lymphomas include extranodal natural killer cell\\/T-cell lymphoma, nasal type, subcutaneous\\u000a panniculitits-like T-cell lymphoma, cutaneous gamma-delta T-cell lymphoma, and cutaneous aggressive epidermotropic CD8+ cytotoxic\\u000a T-cell lymphoma.

Pranil Chandra; Mauricio P. Oyarzo; Dan Jones

340

Regulatory T Cells in Radiotherapeutic Responses  

PubMed Central

Radiation therapy (RT) can extend its influence in cancer therapy beyond what can be attributed to in-field cytotoxicity by modulating the immune system. While complex, these systemic effects can help tip the therapeutic balance in favor of treatment success or failure. Engagement of the immune system is generally through recognition of damage-associated molecules expressed or released as a result of tumor and normal tissue radiation damage. This system has evolved to discriminate pathological from physiological forms of cell death by signaling “danger.” The multiple mechanisms that can be evoked include a shift toward a pro-inflammatory, pro-oxidant microenvironment that can promote maturation of dendritic cells and, in cancer treatment, the development of effector T cell responses to tumor-associated antigens. Control over these processes is exerted by regulatory T cells (Tregs), suppressor macrophages, and immunosuppressive cytokines that act in consort to maintain tolerance to self, limit tissue damage, and re-establish tissue homeostasis. Unfortunately, by the time RT for cancer is initiated the tumor-host relationship has already been sculpted in favor of tumor growth and against immune-mediated mechanisms for tumor regression. Reversing this situation is a major challenge. However, recent data show that removal of Tregs can tip the balance in favor of the generation of radiation-induced anti-tumor immunity. The clinical challenge is to do so without excessive depletion that might precipitate serious autoimmune reactions and increase the likelihood of normal tissue complications. The selective modulation of Treg biology to maintain immune tolerance and control of normal tissue damage, while releasing the “brakes” on anti-tumor immune responses, is a worthy aim with promise for enhancing the therapeutic benefit of RT for cancer.

Schaue, Dorthe; Xie, Michael W.; Ratikan, Josephine A.; McBride, William H.

2012-01-01

341

Heterogeneity of gangliosides among T cell subsets.  

PubMed

Gangliosides are major components of highly organized membrane microdomains or rafts, yet little is known about the role of gangliosides in raft organization. This is also the case of gangliosides in TCR-mediated activation. Comprehensive structural analysis of gangliosides in the primary thymocytes and CD4(+) T and CD8(+) T cells was not achieved due to technical difficulties. We have found that CD8(+) T cells express very high levels of o-series gangliosides, but on the other hand, CD4(+) T cells preferably express a-series gangliosides. In the TCR-dependent activation, CD4(+) T cells selectively require a-series gangliosides, but CD8(+) T cells do require only o-series gangliosides but not a-series gangliosides. Ganglioside GM3 synthase-deficient mice lacking a-series gangliosides neither exhibited the TCR-dependent activation of CD4(+) T nor developed ovalbumin-induced allergic airway inflammation. These findings imply that the distinct expression pattern of ganglioside species in CD4(+) and CD8(+) T cells define the immune function of each T cell subset. PMID:23233133

Inokuchi, Jin-ichi; Nagafuku, Masakazu; Ohno, Isao; Suzuki, Akemi

2013-09-01

342

TNF, but not IL-6 and IL-17, is crucial for the development of T cell-independent psoriasis-like dermatitis in Il1rn-/- mice.  

PubMed

IL-1 is a proinflammatory cytokine consisting of two molecular species, IL-1alpha and IL-1beta, and IL-1R antagonist (gene: Il1rn) is the endogenous suppressor. Il1rn(-/-) mice spontaneously develop autoimmune diseases, such as arthritis and aortitis, and a dermatitis that histologically resembles human psoriasis. The pathogenic mechanisms underlying this dermatitis, however, remain to be elucidated. In this study, we demonstrated that the production of inflammatory cytokines and chemokines was enhanced at the site of inflammation. The development of dermatitis was completely suppressed in Tnfsf1a(-/-) but not in Il6(-/-) mice, similar to that observed in arthritis and aortitis. However, IL-17 deficiency did not affect the development of dermatitis at all, in clear contrast to that of arthritis and aortitis. Different from arthritis and aortitis, adoptive transfer of Il1rn(-/-) T cells did not induce dermatitis in the recipient SCID mice and skin lesions developed in Il1rn(-/-) SCID mice, indicating that T cells are not involved in the development of skin lesions. In support for this, bone marrow cell transplantation experiments showed that TNF produced by skin residential cells, but not bone marrow cell-derived cells, was important for the development of dermatitis. Furthermore, we showed that IL-1 directly enhanced TNF and chemokine expression in keratinocytes. These observations suggest that excess IL-1 signaling directly activates keratinocytes to produce TNF and chemokines, resulting in the development of psoriasis-like skin lesions without the involvement of autoimmunity in Il1rn(-/-) mice. PMID:20610641

Nakajima, Akiko; Matsuki, Taizo; Komine, Mayumi; Asahina, Akihiko; Horai, Reiko; Nakae, Susumu; Ishigame, Harumichi; Kakuta, Shigeru; Saijo, Shinobu; Iwakura, Yoichiro

2010-08-01

343

SELECTION OF MACROPHAGE-RESIS TANT PROGRESSOR TUMOR VARIANTS BY THE NORMAL HOST Requirement for Concomitant T Cell-mediated Immunity  

Microsoft Academic Search

The evolutionary progression from an initial carcinogen-expos ed target cell to a cancer cell is characterized by a series of alterations in heritable phenotypic properties of the cells (1). Obviously, malignant cells that succeed in forming progressive tumors must have developed some means of subverting relevant host defenses and homeostatic control mechanisms. Thus, an analysis of how potentialiy malignant ceils

JAMES L. URBAN; HANS SCHREIBER

344

Immunopathology of experimental Chagas' disease: binding of T cells to Trypanosoma cruzi-infected heart tissue.  

PubMed Central

The immunopathology of Chagas' disease was studied in the experimental model of chronic infection in C57BL/10JT or mice. Sublethal infection with Trypanosoma cruzi, Y strain, induced specific antibodies and a delayed hypersensitivity response to parasite antigens. Mice developed chronic chagasic myocarditis but not skeletal muscle myositis. Binding of T cells to infected heart tissue was investigated during short-term cocultivation of lymphocytes with heart cryostat sections. T cells from infected mice and from normal controls bound equally to myocardium and liver sections from both infected and normal mice. A search in depth was attempted with cells heavily tagged with 99mTc. Labeled T cells from chagasic mice bound to both normal and infected myocardium slices. 99mTc-labeled T cells from controls gave the same binding values. Glass-adherent spleen cells behaved identically to T cells. Prior treatment of the tissue with serum from chronically infected mice did not increase the number of binding cells. Peritoneal macrophages tagged with 99mTc-sulfur colloid also bound to infected myocardium slices. The binding of macrophages was not changed by pretreatment of infected tissue with anti-T, cruzi antibodies. In short, this work did not detect any population of T cells or macrophages which could bind specifically to infected heart tissue to initiate an autoreactive process. Images

Mortatti, R C; Maia, L C; de Oliveira, A V; Munk, M E

1990-01-01

345

The role of the T cell in autoimmune inflammation  

Microsoft Academic Search

T cells, in particular CD4+ T cells, have been implicated in mediating many aspects of autoimmune inflammation. However, current evidence suggests that the role played by CD4+ T cells in the development of rheumatoid inflammation exceeds that of activated proinflammatory T-helper (Th)1 effector cells that drive the chronic autoimmune response. Subsets of CD4+ T cells with regulatory capacity, such as

Alla Skapenko; Jan Leipe; Peter E Lipsky; Hendrik Schulze-Koops

2005-01-01

346

Mucosal and systemic HIV1 Env-specific CD8 + T-cells develop after intragastric vaccination with a Salmonella Env DNA vaccine vector  

Microsoft Academic Search

CD8+ T-cell responses provide beneficial antiviral immunity against human immunodeficiency virus 1 (HIV-1). In this study, we show that intragastric vaccination with a Salmonella HIV-1 Env DNA vaccine vector generates Env-specific CD8+ T-cells, both in mucosal and systemic lymphoid tissue. By contrast, intramuscular vaccination with the Env DNA vaccine alone only induced systemic CD8+ T-cells. To our knowledge, this is

Mohamed T. Shata; Marvin S. Reitz Jr.; Anthony L. DeVico; George K. Lewis; David M. Hone

2001-01-01

347

Selectively Increased Expression and Functions of Chemokine Receptor CCR9 on CD4 T Cells from Patients with T-Cell Lineage Acute Lymphocytic Leukemia1  

Microsoft Academic Search

In a total of 38 typical T-cell lineage acute lymphocytic leukemia (T-ALL) and T-cell lineage chronic lymphocytic leukemia (T-CLL) cases investigated, we found that CC chemokine receptor CCR9 was selectively and frequently expressed on T-ALL CD4 T cells, was moderately ex- pressed on T-CLL CD4 T cells, and was rarely expressed on normal CD4 T cells. These findings were demonstrated

Zhang Qiuping; Li Qun; Hu Chunsong; Zhang Xiaolian; Huang Baojun; Yang Mingzhen; Lao Chengming; He Jinshen; Gao Qingping; Zhang Kejian; Sun Zhimin; Zhang Xuejun; Liu Junyan; Tan Jinquan

348

Human V?9V?2 T cells specifically recognize and kill acute myeloid leukemic blasts.  

PubMed

V?9V?2 T cells are attractive candidates for antileukemic activity. The analysis of V?9V?2 T cells in newly diagnosed acute myeloid leukemia (AML) patients revealed that their absolute cell numbers were normal in the blood as well as in the bone marrow but showed a striking imbalance in the differentiation subsets, with preponderance of the effector memory population. This unusual phenotype was restored after removal of leukemic cells in patients, which reached complete remission after chemotherapy, suggesting that leukemic cells might be involved in the alteration of ?? T cell development in AML. Accordingly, coculture between AML cells and V?9V?2 T cells induced selection of effector cells. In accordance with their effector memory status, in vitro proliferation of V?9V?2 T cells was reduced compared with normal controls. Nevertheless, V?9V?2 T cells efficiently killed autologous AML blasts via the perforin/granzyme pathway. The ligands for DNAM-1 were expressed by AML cells. We showed that killing of AML blasts was TCR and DNAM-1 dependent. Using a xenotransplantation murine model, we showed that V?9V?2 T cells homed to the bone marrow in close proximity of engrafted leukemic cells and enhanced survival. These data demonstrate that V?9V?2 T cells are endowed with the ability to interact with and eradicate AML blasts both in vitro and in a mouse model. Collectively, our data revealed that V?9V?2 T cells have a potent antileukemic activity provided that optimal activation is achieved, such as with synthetic TCR agonists. This study enhances the interest of these cells for therapeutic purposes such as AML treatment. PMID:22467661

Gertner-Dardenne, Julie; Castellano, Remy; Mamessier, Emilie; Garbit, Slaveia; Kochbati, Eloïse; Etienne, Anne; Charbonnier, Aude; Collette, Yves; Vey, Norbert; Olive, Daniel

2012-05-01

349

TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8+ T-cell differentiation.  

PubMed

CD8(+) T-cell development in the thymus generates a predominant population of conventional naive cells, along with minor populations of "innate" T cells that resemble memory cells. Recent studies analyzing a variety of KO or knock-in mice have indicated that impairments in the T-cell receptor (TCR) signaling pathway produce increased numbers of innate CD8(+) T cells, characterized by their high expression of CD44, CD122, CXCR3, and the transcription factor, Eomesodermin (Eomes). One component of this altered development is a non-CD8(+) T cell-intrinsic role for IL-4. To determine whether reduced TCR signaling within the CD8(+) T cells might also contribute to this pathway, we investigated the role of the transcription factor, IFN regulatory factor 4 (IRF4). IRF4 is up-regulated following TCR stimulation in WT T cells; further, this up-regulation is impaired in T cells treated with a small-molecule inhibitor of the Tec family tyrosine kinase, IL-2 inducible T-cell kinase (ITK). In contrast to WT cells, activation of IRF4-deficient CD8(+) T cells leads to rapid and robust expression of Eomes, which is further enhanced by IL-4 stimulation. In addition, inhibition of ITK together with IL-4 increases Eomeso up-regulation. These data indicate that ITK signaling promotes IRF4 up-regulation following CD8(+) T-cell activation and that this signaling pathway normally suppresses Eomes expression, thereby regulating the differentiation pathway of CD8(+) T cells. PMID:23011795

Nayar, Ribhu; Enos, Megan; Prince, Amanda; Shin, Hyunmu; Hemmers, Saskia; Jiang, Jian-kang; Klein, Ulf; Thomas, Craig J; Berg, Leslie J

2012-10-01

350

Maintenance of peripheral T cell responses during Mycobacterium tuberculosis infection  

PubMed Central

Fully functional T cells are necessary for the maintenance of protective immunity during chronic infections. However, activated T cells often undergo apoptosis or exhaustion upon chronic stimulation mediated by antigen or inflammation. T cell attrition can be compensated by the production of thymus-derived T cells, although the new naive T cells must undergo T cell priming and differentiation under conditions different from those encountered during acute infection. We have used a murine model of Mycobacterium tuberculosis (Mtb) infection to address how the activation and differentiation of new thymic emigrants is affected by chronic inflammation, and whether the newly developed effector T cells help to maintain peripheral T cell responses. Although new thymic emigrants contributed to the peripheral T cell response early during acute Mtb infection, the relative contribution of new effector T cells to the peripheral CD4 and CD8 T cell pools declined during chronic infection. The decline in new T cell recruitment was a consequence of quantitative and/or qualitative changes in antigen presentation, as during chronic infection both the priming and expansion of naïve T cells was inefficient. Thus, although thymic tolerance is not a major factor that limits protective T cell responses, the chronic environment does not efficiently support naive T cell priming and accumulation during Mtb infection. These studies support our previous findings that long-term protective T cell response can be maintained indefinitely in the periphery, but also suggest that the perturbation of homeostasis during chronic inflammatory responses may elicit immune pathology mediated by new T cells.

Reiley, William W.; Wittmer, Susan T.; Ryan, Lynn M.; Eaton, Sheri M.; Haynes, Laura; Winslow, Gary M.; Woodland, David L.

2012-01-01

351

T-cell Subset Regulation in Atopy  

Microsoft Academic Search

Presentation of processed allergen by antigen-presenting cells to T-helper (Th) lymphocytes, which is influenced costimulatory\\u000a signals, cytokines, chemokines, and regulatory T cells (Tregs), determines the development of different types of T-cell immunity.\\u000a The discovery of Tregs revolutionized the primary concepts of immune regulation interpreted within the framework of a binary\\u000a Th1\\/Th2 paradigm. Tregs play a central role in the maintenance

Marek Jutel; Cezmi A. Akdis

2011-01-01

352

CMV-specific T cell therapy  

Microsoft Academic Search

Human cytomegalovirus (CMV) infection continues to be one of the most important and life threatening complications after allogeneic stem cell transplantation (SCT).The reconstitution of CMV-specific T cell responses after SCT has been demonstrated to be protective against the development of CMV disease.To improve T cell immunity against CMV in bone marrow transplant patients, different strategies were explored. On one hand,

Hermann Einsele; Markus Kapp; Götz Ulrich Grigoleit

2008-01-01

353

Protein kinase D2 has a restricted but critical role in T-cell antigen receptor signalling in mature T-cells  

PubMed Central

PKD (protein kinase D) 2 is a serine/threonine kinase activated by diacylglycerol in response to engagement of antigen receptors in lymphocytes. To explore PKD2 regulation and function in TCR (T-cell antigen receptor) signal transduction we expressed TCR complexes with fixed affinity for self antigens in the T-cells of PKD2-null mice or mice deficient in PKD2 catalytic activity. We also developed a single cell assay to quantify PKD2 activation as T-cells respond to developmental stimuli or engagement of ?/? TCR complexes in vivo. Strikingly, PKD2 loss caused increases in thymic output, lymphadenopathy and splenomegaly in TCR transgenic mice. The precise magnitude and timing of PKD2 activation during T-cell development is thus critical to regulate thymic homoeostasis. PKD2-null T-cells that exit the thymus have a normal transcriptome, but show a limited and abnormal transcriptional response to antigen. Transcriptional profiling reveals the full consequences of PKD2 loss and maps in detail the selective, but critical, function for PKD2 in signalling by ?/? mature TCR complexes in peripheral T-cells.

Navarro, Maria N.; Sinclair, Linda V.; Feijoo-Carnero, Carmen; Clarke, Rosemary; Matthews, Sharon A.; Cantrell, Doreen A.

2012-01-01

354

MURINE MODELS OF LUPUS INDUCED BY HYPOMETHYLATED T CELLS  

PubMed Central

CD4+ T cell DNA hypomethylation may contribute to the development of drug induced and idiopathic human lupus. Inhibiting DNA methylation in mature CD4+ T cells causes MHC-specific autoreactivity in vitro. The lupus-inducing drugs hydralazine and procainamide also inhibit T cell DNA methylation and induce autoreactivity, and T cells from patients with active lupus have hypomethylated DNA and a similarly autoreactive T cell subset. Further, T cells treated with DNA methylation inhibitors demethylate the same sequences that demethylate in T cells from patients with active lupus. The pathologic significance of the autoreactivity induced by inhibiting T cell DNA methylation has been tested by treating murine T cells in vitro with drugs which modify DNA methylation, then injecting the cells into syngeneic female mice. Mice receiving CD4+ T cells demethylated by a variety of agents including procainamide and hydralazine develop a lupus-like disease. Further, transgenic mice with an inducible T cell DNA methylation defect also develop lupus-like autoimmunity. This chapter describes the protocols for inducing autoreactivity in murine T cells in vitro, and inducing autoimmunity in vivo using an adoptive transfer approach or transgenic animal models.

Richardson, Bruce; Sawalha, Amr H; Ray, Donna; Yung, Raymond

2014-01-01

355

CD4 T Cells Promote Rather than Control Tuberculosis in the Absence of PD-1-Mediated Inhibition  

PubMed Central

Although CD4 T cells are required for host resistance to Mycobacterium tuberculosis, they may also contribute to pathology. In this study, we examine the role of the inhibitory receptor PD-1 and its ligand PD-L1 during M. tuberculosis infection. After aerosol exposure, PD-1 knockout (KO) mice develop high numbers of M. tuberculosis-specific CD4 T cells but display markedly increased susceptibility to infection. Importantly, we show that CD4 T cells themselves drive the increased bacterial loads and pathology seen in infected PD-1 KO mice, and PD-1 deficiency in CD4 T cells is sufficient to trigger early mortality. PD-L1 KO mice also display enhanced albeit less severe susceptibility, indicating that T cells are regulated by multiple PD ligands during M. tuberculosis infection. M. tuberculosis-specific CD8 T cell responses were normal in PD-1 KO mice, and CD8 T cells only had a minor contribution to the exacerbated disease in the M. tuberculosis-infected PD-1 KO and PD-L1 KO mice. Thus, in the absence of the PD-1 pathway, M. tuberculosis benefits from CD4 T cell responses, and host resistance requires inhibition by PD-1 to prevent T cell-driven exacerbation of the infection.

Barber, Daniel L.; Mayer-Barber, Katrin D.; Feng, Carl G.; Sharpe, Arlene H.; Sher, Alan

2014-01-01

356

Mechanisms of T-Cell Activation by Human T-Cell Lymphotropic Virus Type I  

PubMed Central

The interactions between human T-cell lymphotropic virus type I (HTLV-I) and the cellular immune system can be divided into viral interference with functions of the infected host T cell and the subsequent interactions between the infected T cell and the cellular immune system. HTLV-I-mediated activation of the infected host T cell is induced primarily by the viral protein Tax, which influences transcriptional activation, signal transduction pathways, cell cycle control, and apoptosis. These properties of Tax may well explain the ability of HTLV-I to immortalize T cells. It is not clear, though, how HTLV-I induces T-cell transformation (interleukin-2 [IL-2] independence). Recent evidence suggests that Tax may promote the G1- to S-phase transition, although this may involve additional proteins. A role for other viral proteins that may constitutively activate the IL-2 receptor pathway has also been suggested. By virtue of their activated state, HTLV-I-infected T cells can nonspecifically activate resting, uninfected T cells via virus-mediated upregulation of adhesion molecules. This may favor viral dissemination. Moreover, the induction of a remarkably high frequency of antiviral CD8+ T cells does not appear to eliminate the infection. Indeed, individuals with a high frequency of virus-specific CD8+ T cells have a high viral load, indicating a state of chronic immune system stimulation. Thus, while an activated immune system is needed to eradicate the infection, the spread of the HTLV-I is also accelerated under these conditions. A detailed knowledge of the molecular interactions between virus-specific CD8+ T cells and immunodominant viral epitopes holds promise for the development of specific antiviral therapy.

Hollsberg, Per