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Type 1 diabetes (T1D) is a chronic autoimmune condition characterized by hyperglycemia resulting from the destruction of insulin-producing β-cells that is traditionally deemed irreversible, but partial remission (PR) with temporary reversal of hyperglycemia is sometimes observed. Here we use single-cell RNA sequencing to delineate the immune cell landscape across patients in different T1D stages. Together with cohort validation and functional assays, we observe dynamic changes in TIGIT+CCR7− Tregs and CD226+CCR7−CD8+ cytotoxic T cells during the peri-remission phase. Machine learning algorithms further identify TIGIT+CCR7− Tregs and CD226+CD8+ T cells as biomarkers for β-cell function decline in a predictive model, while cell communication analysis and in vitro assays suggest that TIGIT+CCR7− Tregs may inhibit CD226+CCR7−CD8+ T cells via TGF-β signaling. Lastly, in both cyclophosphamide-induced and streptozotocin (STZ)-induced mouse diabetes models, CD226 inhibition postpones insulitis onset and reduces hyperglycemia severity. Our results thus identify two interrelated immune cell subsets that may serve as biomarkers for monitoring disease progression and targets for therapeutic intervention of T1D. Type 1 diabetes (T1D) manifests as hyperglycemia, with spontaneous remission occasionally observed, but the underneath mechanisms are unclear. Here the authors analyses patients at different stages to find two populations of immune cells correlating with disease progression or remission, while results from mouse diabetes models validate these observations. [ABSTRACT FROM AUTHOR]

The T cell lineage–restricted protein THEMIS plays a critical role in T cell development at the positive selection stage. In the SHP1 activation model, THEMIS is proposed to enhance the activity of the tyrosine phosphatase SHP1 (encoded by Ptpn6), thereby dampening T cell antigen receptor (TCR) signaling and preventing the inappropriate negative selection of CD4+CD8+ thymocytes by positively selecting ligands. In contrast, in the SHP1 inhibition model, THEMIS is proposed to suppress SHP1 activity, rendering CD4+CD8+ thymocytes more sensitive to TCR signaling initiated by low-affinity ligands to promote positive selection. We sought to resolve the controversy regarding the molecular function of THEMIS. We found that the defect in positive selection in Themis−/− thymocytes was ameliorated by pharmacologic inhibition of SHP1 or by deletion of Ptpn6 and was exacerbated by SHP1 overexpression. Moreover, overexpression of SHP1 phenocopied the Themis−/− developmental defect, whereas deletion of Ptpn6, Ptpn11 (encoding SHP2), or both did not result in a phenotype resembling that of Themis deficiency. Last, we found that thymocyte negative selection was not enhanced but was instead impaired in the absence of THEMIS. Together, these results provide evidence favoring the SHP1 inhibition model, supporting a mechanism whereby THEMIS functions to enhance the sensitivity of CD4+CD8+ thymocytes to TCR signaling, enabling positive selection by low-affinity, self-ligand–TCR interactions. THEMIS shuts down SHP1 in thymocytes: In the thymus, the exposure of CD4 and CD8 double-positive (DP) thymocytes to self-peptide ligands that stimulate the T cell receptor (TCR) determines their fate. Insufficient TCR signaling results in death by neglect; excessive signaling leads to death by apoptosis to remove self-reactive cells; and sufficient signaling enables the positive selection of the thymocytes into CD4 or CD8 single-positive T cells. Mice deficient in the protein THEMIS exhibit failed thymocyte positive selection. Choi et al. showed that knockout of the inhibitory tyrosine phosphatase SHP1 reversed this defect in Themis knockout mice. Consistent with a model in which THEMIS inhibits SHP1 activity, overexpression of SHP1 phenocopied the effect of loss of THEMIS. In addition, DP thymocyte negative selection was impaired in the absence of THEMIS. Together, these findings suggest that THEMIS inhibits SHP1 in DP thymocytes to enhance their sensitivity to TCR stimulation by self-peptides. —JFF [ABSTRACT FROM AUTHOR]

Epigenetic regulators are pivotal factors that influence and control T cell development. Recent findings continue to reveal additional elements of epigenetic modifications that play significant and crucial roles at different stages of T cell development. Through gaining a better understanding of the various epigenetic factors that influence the formation and survival of maturing T cells, new therapies can potentially be developed to combat diseases caused by dysregulated epigenetic chromatin modifications. In this review, we summarize the recent studies which shed light on the epigenetic regulation of T cell development especially at the critical stage of β-selection. [ABSTRACT FROM AUTHOR]

Signals that determine the differentiation of naïve CD4+ T helper (TH) cells into specific effector cell subsets are primarily stimulated by cytokines, but additional signals are required to adjust the magnitude of TH cell responses and set the balance between effective immunity and immunological tolerance. By inducing the post-thymic deletion of the T cell lineage signaling protein THEMIS, we showed that THEMIS promoted the development of optimal type 1 immune responses to foreign antigens but stimulated signals that favored encephalitogenic responses to self-neuroantigens. THEMIS was required to stimulate the expression of the gene encoding the transcriptional regulator T-BET and the production of the cytokine interferon-γ (IFN-γ), and it enhanced the ability of encephalitogenic CD4+ T cells to migrate into the central nervous system. Consistently, analysis of THEMIS expression in polarized CD4+ T cells showed that THEMIS was selectively increased in abundance in TH1 cells. The stimulation of predifferentiated effector CD4+ T cells with antigen-presenting cells revealed a stimulatory function for THEMIS on type 1 cytokine responses, similar to those observed ex vivo after immunization. In contrast, THEMIS exerted opposing effects on naïve CD4+ T cells in vitro by inhibiting the T cell receptor (TCR)–mediated signals that lead to TH1 cell responses. These data suggest that THEMIS exerts TCR-independent functions in effector T cells, which increase the magnitude of normal and pathogenic TH1 cell–mediated responses. THEMIS in T cells: Naïve T cells integrate antigen-dependent signals through their T cell receptor (TCR) and cytokine signals to differentiate into distinct T helper (TH) cell subsets with specialized immune functions. The T cell signaling protein THEMIS is important for T cell development. Yang et al. disrupted Themis in mice after thymic selection to investigate the function of THEMIS in peripheral T cells. Among different TH cell subsets, THEMIS promoted the function of only TH1 cells, and it enhanced the encephalitogenic responses of T cells in a mouse model of autoimmunity. However, THEMIS had opposing effects on TCR-dependent signaling in naïve T cells in vitro, suggesting that THEMIS signaling is context dependent and that these inhibitory effects are overcome during immune responses in vivo by TCR-independent signaling by THEMIS that promotes T cell effector function. [ABSTRACT FROM AUTHOR]

CD5 is constitutively expressed on all T cells and is a negative regulator of lymphocyte function. However, the full extent of CD5 function in immunity remains unclear. CD5 deficiency impacts thymic selection and extra-thymic regulatory T cell generation, yet CD5 knockout was reported to cause no immune pathology. Here we show that CD5 is a key modulator of gut immunity. We generated mice with inducible CD5 knockdown (KD) in the autoimmune-prone nonobese diabetic (NOD) background. CD5 deficiency caused T celldependent wasting disease driven by chronic gut immune dysregulation. CD5 inhibition also exacerbated acute experimental colitis. Mechanistically, loss of CD5 increased phospho-Stat3 levels, leading to elevated IL-17A secretion. Our data reveal a new facet of CD5 function in shaping the T cell cytokine profile. [ABSTRACT FROM AUTHOR]

Immature T cells undergo a process of positive selection in the thymus when their new T cell receptor (TCR) engages and signals in response to self-peptides. As the T cell matures, a slew of negative regulatory molecules, including the inhibitory surface glycoprotein CD5, are up-regulated in proportion to the strength of the self-peptide signal. Together these regulators dampen TCR-proximal signaling and help avoid any subsequent peripheral activation of T cells by self-peptides. Paradoxically, antigen-specific T cells initially expressing more CD5 (CD5hi) have been found to better persist as effector/memory cells after a peripheral challenge. The molecular mechanisms underlying such a duality in CD5 function is not clear. We found that CD5 alters the basal activity of the NF-κB signaling in resting peripheral T cells. When CD5 was conditionally ablated, T cells were unable to maintain higher expression of the cytoplasmic NF-κB inhibitor IκBα. Consistent with this, resting CD5hi T cells expressed more of the NF-κB p65 protein than CD5lo cells, without significant increases in transcript levels, in the absence of TCR signals. This posttranslationally stabilized cellular NF-κB depot potentially confers a survival advantage to CD5hi T cells over CD5lo ones. Taken together, these data suggest a two-step model whereby the strength of self-peptide-induced TCR signal lead to the up-regulation of CD5, which subsequently maintains a proportional reserve of NF-κB in peripheral T cells poised for responding to agonistic antigen-driven T cell activation. [ABSTRACT FROM AUTHOR]

CD5 is characterized as an inhibitory coreceptor with an important regulatory role during T cell development. The molecular mechanism by which CD5 operates has been puzzling and its function in mature T cells suggests promoting rather than repressing effects on immune responses. Here, we combined quantitative mass spectrometry and genetic studies to analyze the components and the activity of the CD5 signaling machinery in primary T cells. We found that T cell receptor (TCR) engagement induces the selective phosphorylation of CD5 tyrosine 429, which serves as a docking site for proteins with adaptor functions (c-Cbl, CIN85, CRKL), connecting CD5 to positive (PI3K) and negative (UBASH3A, SHIP1) regulators of TCR signaling. c-CBL acts as a coordinator in this complex enabling CD5 to synchronize positive and negative feedbacks on TCR signaling through the other components. Disruption of CD5 signalosome in mutant mice reveals that it modulates TCR signal outputs to selectively repress the transactivation of Foxp3 and limit the inopportune induction of peripherally induced regulatory T cells during immune responses against foreign antigen. Our findings bring insights into the paradigm of coreceptor signaling, suggesting that, in addition to providing dualistic enhancing or dampening inputs, coreceptors can engage concomitant stimulatory and inhibitory signaling events, which act together to promote specific functional outcomes. [ABSTRACT FROM AUTHOR]

Primary T-cell acute lymphoblastic leukemia (T-ALL) cells require stromal-derived signals to survive. Although many studies have identified cell-intrinsic alterations in signaling pathways that promote T-ALL growth, the identity of endogenous stromal cells and their associated signals in the tumor microenvironment that support T-ALL remains unknown. By examining the thymic tumor microenvironments in multiple murine T-ALL models and primary patient samples, we discovered the emergence of prominent epithelial-free regions, enriched for proliferating tumor cells and dendritic cells (DCs). Systematic evaluation of the functional capacity of tumor-associated stromal cells revealed that myeloid cells, primarily DCs, are necessary and sufficient to support T-ALL survival ex vivo. DCs support T-ALL growth both in primary thymic tumors and at secondary tumor sites. To identify a molecular mechanism by which DCs support T-ALL growth,we first performed gene expression profiling,which revealed up-regulation of platelet-derived growth factor receptor beta (Pdgfrb) and insulin-like growth factor I receptor (Igf1r) on T-ALL cells, with concomitant expression of their ligands by tumor-associated DCs. Both Pdgfrb and Igf1r were activated in ex vivo T-ALL cells, and coculture with tumor-associated, but not normal thymic DCs, sustained IGF1R activation. Furthermore, IGF1R signaling was necessary for DCmediated T-ALL survival. Collectively, these studies provide the first evidence that endogenous tumor-associated DCs supply signals driving T-ALL growth, and implicate tumor-associated DCs and their mitogenic signals as auspicious therapeutic targets. [ABSTRACT FROM AUTHOR]

The LMO2 oncogene is deregulated in the majority of human T-cell leukemia cases and in most gene therapy-induced T-cell leukemias. We made transgenic mice with enforced expression of Lmo2 in T-cells by the CD2 promoter/enhancer. These transgenic mice developed highly penetrant T-ALL by two distinct patterns of gene expression: one in which there was concordant activation of Lyl1, Hhex, and Mycn or alternatively, with Notch1 target gene activation. Most strikingly, this gene expression clustering was conserved in human Early T-cell Precursor ALL (ETP-ALL), where LMO2, HHEX, LYL1, and MYCN were most highly expressed. We discovered that HHEX is a direct transcriptional target of LMO2 consistent with its concordant gene expression. Furthermore, conditional inactivation of Hhex in CD2-Lmo2 transgenic mice markedly attenuated T-ALL development, demonstrating that Hhex is a crucial mediator of Lmo2's oncogenic function. The CD2-Lmo2 transgenic mice offer mechanistic insight into concordant oncogene expression and provide a model for the highly treatment-resistant ETP-ALL subtype. [ABSTRACT FROM AUTHOR]

LIM domain only 2 ( Lmo2) is frequently deregulated in sporadic and gene therapy-induced acute T-cell lymphoblastic leukemia (T-ALL) where its overexpression is an important initiating mutational event. In transgenic and retroviral mouse models, Lmo2 expression can be enforced in multiple hematopoietic lineages but leukemia only arises from T cells. These data suggest that Lmo2 confers clonal growth advantage in T-cell progenitors. We analyzed proliferation, differentiation, and cell death in CD2-Lmo2 transgenic thymic progenitor cells to understand the cellular effects of enforced Lmo2 expression. Most impressively, Lmo2 transgenic T-cell progenitor cells were blocked in differentiation, quiescent, and immortalized in vitro on OP9-DL1 stromal cells. These cellular effects were concordant with a transcriptional signature in Lmo2 transgenic T-cell progenitor cells that is also present in hematopoietic stem cells (HSCs) and early T-cell precursor ALL. These results are significant in light of the crucial role of Lmo2 in the maintenance of the HSC. The cellular effects and transcriptional effects have implications for LMO2-dependent leukemogenesis and the treatment of LMO2-induced T-ALL. S TEM C ELLS 2013;31:882-894 [ABSTRACT FROM AUTHOR]

Thymocytes must transit at least two distinct developmental checkpoints, governed by signals that emanate from either the pre-T celleceptor (pre-TCR) or the TCR to the small G protein Ras before emerging as functional T lymphocytes. Recent studies have shown aole for the Ras guanine exchange factor (RasGEF) Sos1 at the pre-TCR checkpoint. At the second checkpoint, the quality of signaling through the TCR is interrogated to ensure the production of an appropriate T cell repertoire. Although RasGRP1 is the only confirmed RasGEF required at the TCR checkpoint, current models suggest that the intensity and character of Ras activation,acilitated by both Sos and RasGRP1, will govern the boundary between survival (positive selection) and death (negative selection) athis stage. Using mouse models, we have assessed the independent and combined roles for the RasGEFs Sos1, Sos2, and RasGRP1 during thymocyte development. Although Sos1 was the dominant RasGEF at the pre-TCR checkpoint, combined Sos1/RasGRP1 deletion was required to effectively block development at this stage. Conversely, while RasGRP1 deletion efficiently blocked positive selection, combined RasGRP1/Sos1 deletion was required to block negative selection. This functional redundancy in RasGEFs during negative selection may act as a failsafe mechanism ensuring appropriate central tolerance. [ABSTRACT FROM AUTHOR]

Background & Aims: Induction of oral immune tolerance (OT) blocks proinflammatory responses to orally administered antigens and might be used to treat autoimmune conditions. We investigated whether gut-tropic T cells that express the integrin α4β7 and the chemokine receptor CCR9 are required for OT. Methods: Skin delayed-type hypersensitivity and experimental autoimmune encephalomyelitis were used to monitor OT in mice. To assess the role of receptors that mediate localization of lymphocytes to the gut (gut-homing receptors) in induction of OT, we studied CCR9 −/− and β7 −/− mice and also blocked the α4β7 ligand MAdCAM-1 in wild-type mice. We used DEREG and Scurfy mice to assess the role of Foxp3+ regulatory T cells (Treg) and IL-10 −/− and IL-10Rβ −/− mice to examine the role of interleukin (IL)-10 in induction of OT. Results: OT could not be induced in CCR9 −/− or β7 −/− mice, or when MAdCAM-1 was blocked in wild-type mice, indicating that gut-homing receptors are required for oral tolerization. Consistent with the role of all-trans retinoic acid in inducing gut-homing T cells, OT could not be induced in mice depleted of vitamin A. OT was rescued in CCR9 −/− mice following adoptive transfer of wild-type T cells, but not CCR9 −/− or β7 −/− T cells. Gut-homing T cells are therefore necessary and sufficient to induce OT. Wild-type Treg and IL-10 were required to restore OT to CCR9 −/− mice, indicating that homing and functional differentiation of IL-10–producing Treg in the gut is required for OT. Conversely, transfer of CCR9 −/− or β7 −/− T cells to wild-type mice partially inhibited OT. Conclusions: Expression of CCR9 and α4β7 on T cells and their subsequent localization to the gut is required for induction of OT in mice. Therapies designed to block gut-homing receptors might, under some conditions, interfere with normal tolerogenic mechanisms in the intestinal mucosa. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The thymus produces self-tolerant functionally competent T cells. This process involves the import of multipotent haematopoietic progenitors that are then signalled to adopt the T cell fate. Expression of T cell-specific genes, including those encoding the T cell receptor (TCR), is followed by positive and negative selection and the eventual export of mature T cells. Significant progress has been made in elucidating the signals that direct progenitor cell trafficking to, within and out of the thymus. These advances are the subject of this Review, with a particular focus on the role of reciprocal cooperative and regulatory interactions between TCR- and chemokine receptor-mediated signalling. [ABSTRACT FROM AUTHOR]

During positive selection, thymocytes transition through a stage during which T cell antigen receptor (TCR) signaling controls CD4-versus-CD8 lineage 'choice' and subsequent maturation. Here we describe a previously unknown T cell–specific protein, Themis, that serves a distinct function during this stage. In Themis−/− mice, thymocyte selection was impaired and the number of transitional CD4+CD8int thymocytes as well as CD4+ or CD8+ single-positive thymocytes was lower. Notably, although we detected no overt TCR-proximal signaling deficiencies, Themis−/− CD4+CD8int thymocytes showed developmental defects consistent with attenuated signaling that were reversible by TCR stimulation. Our results identify Themis as a critical component of the T cell developmental program and suggest that Themis functions to sustain and/or integrate signals required for proper lineage commitment and maturation. [ABSTRACT FROM AUTHOR]

Bam32 (B lymphocyte adapter molecule of 32 kDa) is an adapter protein expressed in some hematopoietic cells including B and T lymphocytes. It was previously shown that Bam32-deficient mice have defects in various aspects of B cell activation including B cell receptor (BCR)-induced Erk activation, BCR-induced proliferation and T-independent antibody responses. In this study, we have examined the role of Bam32 in T cell activation using Bam32-deficient mice. By comparing CD4+ T cells from lymph nodes of wild-type and Bam32-deficient mice, we found that Bam32 was required for optimal TCR-induced Erk activation, cytokine production, proliferation and actin-mediated spreading of CD4+ T cells. These results indicate a novel pathway to Erk activation in T cells involving the adapter protein Bam32. [ABSTRACT FROM PUBLISHER]

Since the discovery of γδ T cells two decades ago, considerable effort has been made to understand their developmental program, their antigen specificity, and their contribution to the immune response. In this review, we focus on what is known about γδ T-cell development and on the advances that have been made in determining which genes are required. In addition, we compare the genetic requirements for αβ and γδ T-cell development with the hope of gaining a better picture of the signaling pathways that govern the development of γδ lineage cells. [ABSTRACT FROM AUTHOR]

Prevailing knowledge dictates that naive αβ T cells require activation in lymphoid tissues before differentiating into effector or memory T cells capable of trafficking to nonlymphoid tissues. Here we demonstrate that CD8+ recent thymic emigrants (RTEs) migrated directly into the small intestine. CCR9, CCL25 and α4β7 integrin were required for gut entry of CD8+ RTEs. After T cell receptor stimulation, intestinal CD8+ RTEs proliferated and acquired a surface phenotype resembling that of intraepithelial lymphocytes. CD8+ RTEs efficiently populated the gut of lymphotoxin-α-deficient mice, which lack lymphoid organs. These studies challenge the present understanding of naive αβ T cell trafficking and suggest that RTEs may be involved in maintaining a diverse immune repertoire at mucosal surfaces. [ABSTRACT FROM AUTHOR]

The T cell receptor for antigen (TCR) complex is organized into two functional domains: the antigen-binding clonotypic heterodimer and the signal-transducing invariant CD3 and TCRζ chains. In most vertebrates, there are two different clonotypic heterodimers (TCRαβ and TCRγδ) that define the αβ and γδ T cell lineages, respectively. αβ - and γδTCRs also differ in their invariant chain subunit composition, in that αβTCRs contain CD3γε and CD3γε dimers, whereas γδTCRs contain only CD3γε dimers. This difference in subunit composition of the αβ- and γδTCRs raises the question of whether the stoichiometries of these receptor complexes are different. As the stoichiometry of the murine γδTCR has not been previously investigated, we used two quantitative immunofluorescent approaches to determine the valency of TCRγδ heterodimers and CD3γε dimers in surface murine γδTCR complexes. Our results support a model of murine γδTCR stoichiometry in which there are two CD3γε dimers for every TCRγδ heterodimer. [ABSTRACT FROM AUTHOR]

Linker for activation of T cells (LAT) is a scaffolding adaptor protein that is critical for T cell development and function. A mutation of LAT (Y136F) that disrupts phospholipase C-γ1 activation and subsequent calcium influx causes a partial block in T cell development and leads to a severe lymphoproliferative disease in homozygous knock-in mice. One possible contribution to the fatal disease of LAT Y13GF knock-in mice could be from autoreactive T cells generated in these mice because of altered thymocyte selection. To examine the impact of the LAT Y136F mutation on thymocyte positive and negative selection, we bred this mutation onto the HY T cell receptor (TCR) transgenic, recombination activating gene-2 knockout background. Female mice with this genotype showed a severe defect in positive selection, whereas male mice exhibited a phenotype resembling positive selection (i.e., development and survival of CD8hi HY TCR-specific T cells) instead of negative selection. These results support the hypothesis that in non-TCR transgenic, LAT Y136F knock-in mice, altered thymocyte selection leads to the survival and proliferation of autoreactive T cells that would otherwise be negatively selected in the thymus. [ABSTRACT FROM AUTHOR]

Adapter molecules in a variety of signal transduction systems link receptors to a limited number of commonly used downstream signaling pathways. During T-cell development and mature T-cell effector function, a multi-chain receptor (the pre-T-cell antigen receptor or the T-cell antigen receptor) activates several protein tyrosine kinases. Receptor and kinase activation is linked to distal signaling pathways (PLC-γ1 activation, Ca[sup 2+] influx, PKC activation and Ras/Erk activation) via the adapter protein LAT (Linker for Activation of T cells). Structure/function studies of LAT including expression of selected LAT point mutations in vivo reveals that these multiple pathways are integrated at the level of the LAT adapter. These studies suggest that similar levels of control may be found in other systems where adapter molecules are known to have important functions. [ABSTRACT FROM AUTHOR]

T cell antigen receptor-induced signals are required for normal T cell development and function. Recent studies have investigated the mechanism(s) by which signals of different strengths are converted into distinct cellular fates during thymocyte development. These studies indicate the importance of the strength and duration of signals activated through PLC and PKC pathways in shaping the mature TCR repertoire. [Copyright &y& Elsevier]

The T cell antigen receptor (TCR) is a multimeric complex composed of an antigen-binding clonotypic heterodimer and a signal transducing complex consisting of the CD3 dimers (CD3ϒε and CD3δε) and a TCR-ς homodimer. In all jawed vertebrates there are two T cell lineages, αβ and ϒδ, distinguished by the clonotypic subunits contained within their TCRs (TCR-α and -β or TCR-ϒ and -δ respectively). A third receptor complex, the preTCR, is only expressed on immature T cells. The preTCR, which contains the invariant pre-Tα (pTα) chain in lieu of TCR-α, plays a critical role in the early development of αβ lineage cells. The subunit composition of the signal transducing complexes of the pre-, α&beta:- and ϒδTCRs was previously thought to be identical. However, recent data demonstrate that there are significant differences in the signal transducing complexes of these three TCRs. For example, αβTCRs contain both CD3ϒε and CD3δε dimers, whereas ϒδTCRs contain only CD3ϒε dimers. Moreover, preTCR function appears to be unaffected in the absence of CD3δ, suggesting that CD3δ&epsilon dimers are dispensable for pre-TCR assembly. In this review, we summarize current data relating to the subunit composition of the pre-, αβ- and ϒδTCRs and discuss how these structural differences may impact receptor signaling and αβ/ϒδ lineage determination. [ABSTRACT FROM AUTHOR]

Immature CD4− CD8− thymocytes progress through several developmental steps in the thymus, ultimately emerging as mature CD4+ (helper) or CD8+ (cytotoxic) T cells. Activation of naïve CD4+ and CD8+ T cells in the presence of specific cytokines results in the induction of transcriptional programs that result in their differentiation into effector or memory cells and in the case of CD4+ T cells, the adoption of distinct T-helper fates. Previous studies have shown that histone modification and DNA methylation play important roles in each of these events. More recently, the roles of specific epigenetic regulators in T cell differentiation have been clarified. The identification of the epigenetic modifications and modifiers that control mature T cell differentiation and specification has also provided further insights into how dysregulation of these processes can lead to cancer or autoimmune diseases. In this review, we summarize recent findings that have provided new insights into epigenetic regulation of T cell differentiation in both mice and humans. [ABSTRACT FROM AUTHOR]

Evaluates the importance of zeta in the maturation of T cells. Derivation of zeta-deficient mice from embryonic stem; Examination of endogenous and mutant alleles by Northern (RNA) blotting; Assessment of synthesis of other T cell antigen receptor (TCR) components; Assessment of T cell development in the absence of zeta; Reexamination of the thymuses.

T cell receptor (TCR) β-selection (herein referred to as β-selection) is a pivotal checkpoint in mammalian T cell development when immature CD4–CD8– T-cells (thymocytes) express pre-TCR following successful Tcrb gene rearrangement. At this stage, αβ T cell lineage commitment and allelic exclusion to restrict one β-chain per cell take place and thymocytes undergo a proliferative burst. β-selection is known to be crucially dependent upon synchronized Notch and pre-TCR signaling; however, other necessary inputs have been identified over the past decade, expanding our knowledge and understanding of the β-selection process. In this review, we discuss recent mechanistic findings that have enabled a more detailed decoding of the molecular dynamics of the β-selection checkpoint and have helped to elucidate its role in early T cell development. TCR β-selection is a crucial checkpoint for normal mammalian T cell development. Malfunction of this process can lead to a developmental block and/or predisposition to oncogenic transformation. β-selection enforces αβ lineage commitment. Pre-TCR signals can be triggered autonomously or can be ligand initiated, contributing to TCRβ diversity during β-selection. Coordinated Notch and pre-TCR signaling can result in an optimal proliferative response through the degradation of the cyclin-dependent kinase inhibitor, Cdkn1b, in mice. Distinctive elements of the β-selection process in mice and humans underscore the need for continued research to understand human T cell ontogeny. [ABSTRACT FROM AUTHOR]

A correction to the article "Themis, a T cell-specific Protein Important for Late Thymocyte Development" that was published in the July 13, 2009 issue is presented.

Summary: Signals transduced by T cell antigen receptors (TCRs) have been shown to be critical for αβ and γδ T cell development, but their role in lineage determination remains poorly defined. Two models have been forwarded for αβ/γδ lineage choice: the instructive model and the stochastic model. Recent data, however, are inconsistent with either model. In this study, we devised an experimental system in which lineage fate was controlled exclusively by the γδTCR. We then analyzed the impact of TCR signal strength on αβ/γδ lineage development by altering the surface expression or signaling potential of the γδTCR complex. We found that increasing the γδTCR signal strength favored γδ lineage development, whereas weakening the γδTCR signal favored αβ lineage development. These results support a model in which the strength of the TCR signal is a critical determinant in the lineage fate decision. [Copyright &y& Elsevier]

THEMIS, a recently identified T-lineage-restricted protein, is the founding member of a large metazoan protein family. Gene inactivation studies have revealed a critical requirement for THEMIS during thymocyte positive selection, implicating THEMIS in signaling downstream of the T cell antigen receptor (TCR), but the mechanistic underpinnings of THEMIS function have remained elusive. A previous model posited that THEMIS prevents thymocytes from inappropriately crossing the positive/negative selection threshold by dampening TCR signaling. However, new data suggest an alternative model where THEMIS enhances TCR signaling enabling thymocytes to reach the threshold for positive selection, avoiding death by neglect. We review the data supporting each model and conclude that the preponderance of evidence favors an enhancing function for THEMIS in TCR signaling. [ABSTRACT FROM AUTHOR]

Themisl, a recently identified T cell protein, has a critical function in the generation of mature CD4+CD8- and CD4-CD8+ (CD4 and CD8 single-positive [SP]) thymocytes and T cells. Although Themisl has been shown to bind to the adaptor proteins LAT and Grb2, previous studies have yielded conflicting results regarding whether thymocytes from Themisl-/- mice exhibit TCR-mediated signaling defects. In this study, we demonstrate that, in the absence of Themisl, TCR-mediated signaling is selectively impaired in CD4 SP and CD8 SP thymocytes but is not affected in CD4+CD8+ double-positive thymocytes despite high expression of Themisl in double-positive thymocytes. Like Themisl, Themis2, a related member of the Themis family, which is expressed in B cells and macrophages, contains two conserved cysteine-based domains, a proline-rich region, and a nuclear localization signal. To determine whether Themisl and Themis2 can perform similar functions in vivo, we analyzed T cell development and TCR-mediated signaling in Themisl-/- mice reconstituted with either Themisl or Themis2 transgenes. Notably, Themisl and Themis2 exhibited the same potential to restore T cell development and TCR-mediated signaling in Themisl-/-mice. Both proteins were tyrosine phosphorylated and were recruited within Grb2 signaling complexes to LAT following TCR engagement. These results suggest that conserved molecular features of the Themisl and Themis2 proteins are important for their biological activity and predict that Themisl and Themis2 may perform similar functions in T and B cells, respectively. The Journal of Immunology, 2012, 189: 1154-1161. [ABSTRACT FROM AUTHOR]

Psoriasis is a common immune-mediated chronic inflammatory skin disorder, but the mechanisms of pathogenesis are still poorly understood. IL-23 is expressed in psoriatic skin, and IL-23 injection produces IL-22-dependent psoriasiform changes in mouse skin. Th17 cells produce IL-22 and display CCR6, the CCL20 receptor; CCR6+ T cells and CCL20 are abundant in psoriatic skin. We investigated a possible role for CCR6 in recruiting Th17 cells and producing psoriasiform pathology by injecting IL-23 into the skin of WT and Ccr6-/- mice. Unlike for WT mice, IL-23-injected ears of Ccr6-/- mice showed neither substantial epidermal/dermal changes nor increased Il22 mRNA expression. However, injection of IL-22 yielded equivalent psoriasiform changes in WT and Ccr6-/- mice. Surprisingly, IL-23-injected ears of WT and Ccr6-/- mice contained similar numbers of Th cells able to make IL-17A and/or IL-22. Furthermore, in ears of Rag1-/- mice, IL-23 initially induced skin changes and levels of Il22 mRNA that were indistinguishable from WT mice, revealing at least one non-T cell source for IL-22. We conclude that CCR6 is essential in a model of IL-23-induced, IL-22-mediated dermatitis, which develops in sequential T cell-independent and T cell-dependent phases. These findings reveal an expanded role for CCR6 in IL-23-related responses and identify CCR6 as a potential therapeutic target in psoriasis. [ABSTRACT FROM AUTHOR]

Focuses on the inhibition of T cell development by a linker for activation of T cells (LAT) in mice. Link of polyclonal lymphoproliferation disorder with LAT mutation; Properties of transmembrane scaffolding protein LAT; Role of integrated phospholipase signaling in T cell development and homeostasis.

Summary Lineage-committed αβ and γδ T cells are thought to originate from common intrathymic multipotent progenitors following instructive T cell receptor (TCR) signals. A subset of lymph node and mucosal Vγ2+ γδ T cells is programmed intrathymically to produce IL-17 (Tγδ17 cells), however the role of the γδTCR in development of these cells remains controversial. Here we generated reporter mice for the Tγδ17 lineage-defining transcription factor SOX13 and identified fetal-origin, intrathymic Sox13 + progenitors. In organ culture developmental assays, Tγδ17 cells derived primarily from Sox13 + progenitors, and not from other known lymphoid progenitors. Single cell transcriptome assays of the progenitors found in TCR-deficient mice demonstrated that Tγδ17 lineage programming was independent of γδTCR. Instead, generation of the lineage committed progenitors and Tγδ17 cells was controlled by TCF1 and SOX13. Thus, T lymphocyte lineage fate can be prewired cell-intrinsically and is not necessarily specified by clonal antigen receptor signals. Graphical Abstract Highlights • DN1d thymocyte progenitors are Sox13 hi and express Tγδ17 genes • DN1d cells generate Vγ2+ Tγδ17 cells in developmental assays • DN1d cell transcriptome is programmed independently of γδTCR expression and signaling • SOX13 and TCF7 regulate DN1d cell generation and programming The role of TCR in establishing IL-17 producing γδ T (Tγδ17) cell lineage identity during thymic development remains controversial. Spidale et al. identify a Sox13 hi progenitor to Vγ2+ Tγδ17 cells and demonstrate that progenitor programming is dependent on SOX13 and TCF7 but independent of γδTCR. [ABSTRACT FROM AUTHOR]