PI3 kinase signalling blocks Foxp3 expression by sequestering Foxo factors

Expression of the regulatory T (T reg) cell–associated transcription factor Foxp3 can be induced by signals from the T cell receptor (TCR), interleukin-2 (IL-2), and transforming growth factor (TGF)-β. These signals are integrated by a network involving phosphatidylinositol 3 kinase (PI3K), protein kinase B (PKB; here referred to as Akt), and the mammalian target of rapamycin (mTOR). New studies show that the Foxo proteins Foxo1 and Foxo3a, which are inactivated by Akt, drive Foxp3 expression. These studies therefore explain the negative regulation of Foxp3 by PI3K signaling, and add Foxo proteins to the growing list of nuclear factors capable of modulating Foxp3 expression

The Eδ enhancer controls the generation of CD4−CD8− αβTCR-expressing T cells that can give rise to different lineages of αβ T cells

It is well established that the pre–T cell receptor for antigen (TCR) is responsible for efficient expansion and differentiation of thymocytes with productive TCRβ rearrangements. However, Ptcra- as well as Tcra-targeting experiments have suggested that the early expression of Tcra in CD4−CD8− cells can partially rescue the development of αβ CD4+CD8+ cells in Ptcra-deficient mice. In this study, we show that the TCR Eδ but not Eα enhancer function is required for the cell surface expression of αβTCR on immature CD4−CD8− T cell precursors, which play a crucial role in promoting αβ T cell development in the absence of pre-TCR. Thus, αβTCR expression by CD4−CD8− thymocytes not only represents a transgenic artifact but occurs under physiological conditions

Lineage Diversion of T Cell Receptor Transgenic Thymocytes Revealed by Lineage Fate Mapping

Background: The binding of the T cell receptor (TCR) to major histocompatibility complex (MHC) molecules in the thymus determines fates of $TCR\alpha\beta$ lymphocytes that subsequently home to secondary lymphoid tissue. TCR transgenic models have been used to study thymic selection and lineage commitment. Most TCR transgenic mice express the rearranged $TCR\alpha\beta$ prematurely at the double negative stage and abnormal TCRαβ populations of T cells that are not easily detected in non-transgenic mice have been found in secondary lymphoid tissue of TCR transgenic mice. Methodology and Principal Findings: To determine developmental pathways of TCR-transgenic thymocytes, we used Cre-LoxP-mediated fate mapping and show here that premature expression of a transgenic $TCR\alpha\beta$ diverts some developing thymocytes to a developmental pathway which resembles that of gamma delta cells. We found that most peripheral T cells with the HY-TCR in male mice have bypassed the RORγt-positive $CD4^{+}8^{+}$ (double positive, DP) stage to accumulate either as $CD4^{-}8^{-}$ (double negative, DN) or as $CD8\alpha^{+}$ T cells in lymph nodes or gut epithelium. Likewise, DN $TCR\alpha\beta$ cells in lymphoid tissue of female mice were not derived from DP thymocytes. Conclusion: The results further support the hypothesis that the premature expression of the $TCR\alpha\beta$ can divert DN thymocytes into gamma delta lineage cells

T Cell-Intrinsic and -Extrinsic Contributions of the IFNAR/STAT1-Axis to Thymocyte Survival

STAT1 is an essential part of interferon signaling, and STAT1-deficiency results in heightened susceptibility to infections or autoimmunity in both mice and humans. Here we report that mice lacking the IFNα/β-receptor (IFNAR1) or STAT1 display impaired deletion of autoreactive CD4+CD8+-T-cells. Strikingly, co-existence of WT T cells restored thymic elimination of self-reactive STAT1-deficient CD4+CD8+-T cells. Analysis of STAT1-deficient thymocytes further revealed reduced Bim expression, which was restored in the presence of WT T cells. These results indicate that type I interferons and STAT1 play an important role in the survival of MHC class I-restricted T cells in a T cell intrinsic and non-cell intrinsic manner that involves regulation of Bim expression through feedback provided by mature STAT1-competent T cells

The influence of T cell development on pathogen specificity and autoreactivity

T cells orchestrate adaptive immune responses upon activation. T cell activation requires sufficiently strong binding of T cell receptors on their surface to short peptides derived from foreign proteins bound to protein products of the major histocompatibility (MHC) gene products, which are displayed on the surface of antigen presenting cells. T cells can also interact with peptide-MHC complexes, where the peptide is derived from host (self) proteins. A diverse repertoire of relatively self-tolerant T cell receptors is selected in the thymus. We study a model, computationally and analytically, to describe how thymic selection shapes the repertoire of T cell receptors, such that T cell receptor recognition of pathogenic peptides is both specific and degenerate. We also discuss the escape probability of autoimmune T cells from the thymus.Comment: 12 pages, 7 figure

Identification of CD4−CD8− Double-Negative Natural Killer T Cell Precursors in the Thymus

BACKGROUND: It is well known that CD1d-restricted Valpha14 invariant natural killer T (NKT) cells are derived from cells in the CD4(+)CD8(+) double-positive (DP) population in the thymus. However, the developmental progression of NKT cells in the earlier stages remains unclear, and the possible existence of NKT cell presursors in the earlier stages than DP stage remains to be tested. PRINCIPAL FINDINGS: Here, we demonstrate that NKT cell precursors that express invariant Valpha14-Jalpha18 transcripts but devoid of surface expression of the invariant Valpha14 receptor are present in the late CD4(-)CD8(-) double-negative (DN)4 stage and have the potential to generate mature NKT cells in both in vivo and in vitro experimental conditions. Moreover, the DN4 population in CD1d knock-out (CD1dKO) mice was similar to those with an NKT cell potential in wild-type (WT) C57BL/6 (B6) mice, but failed to develop into NKT cells in vitro. However, these precursors could develop into NKT cells when co-cultured with normal thymocytes or in an in vivo experimental setting, indicating that functional NKT cell precursors are present in CD1dKO mice. CONCLUSIONS: Together, these results demonstrate that thymic DN4 fraction contains NKT cell precursors. Our findings provide new insights into the early development of NKT cells prior to surface expression of the invariant Valpha14 antigen receptor and suggest the possible alternative developmental pathway of NKT cells