Regulation of CD4 T cell Development and Function by BCL11B Transcription Factor

描述（由申请人提供）：双阳性胸腺细胞的命运取决于胸腺皮质上皮细胞上的TCR和自身肽- mhc复合物之间相互作用的强度和持续时间。弱相互作用导致积极的选择和生存信号，使DP胸腺细胞免于被忽视而死亡。阳性选择对免疫功能至关重要，因为这是产生具有有用TCR特异性的T细胞库的过程。然而，对正选择的转录控制知之甚少。我们发现转录因子BCL11B控制着阳性选择的早期步骤，因为去除会导致TCR信号减弱和阳性选择失败。此外，在缺乏BCL11B的情况下，即使在缺乏TCR信号的情况下，DP胸腺细胞的存活率也会降低，这表明BCL11B在DP胸腺细胞的存活控制中起着重要作用。为了支持我们的假设，BCL11B对DP胸腺细胞的阳性选择和存活至关重要，我们有证据表明BCL11B控制与DP胸腺细胞的阳性选择和存活相关的基因表达。此外，在T细胞发育DP阶段缺乏BCL11B的情况下，外周缺乏BCL11B的T淋巴细胞数量减少呈现活化表型，小鼠发生消耗性疾病和结肠炎。成熟T细胞条件去除BCL11B也会导致活化CD4+ T细胞数量增加。这些结果支持了BCL11B调节成熟CD4+ T淋巴细胞的假设。我们拟通过条件诱导小鼠系统和生化研究，探讨BCL11B通过转录调控基因表达调控DP胸腺细胞阳性选择和存活的机制。此外，我们建议确定BCL11B在常规和T调节性CD4+ T细胞中的作用。公共卫生相关声明：这些研究的结果将显著有助于对DP胸腺细胞的阳性选择和存活的分子理解，这两者在产生适当的T细胞以获得充分的免疫反应中起着至关重要的作用。此外，这些研究将有助于了解CD4+ T效应细胞和CD4+ T调节细胞的转录程序，并对自身免疫性疾病具有重要意义。

DESCRIPTION (provided by applicant): The fate of double positive thymocytes is dictated by the strength and duration of the interaction between TCR and self peptide-MHC complex presented on the cortical thymic epithelial cells. A weak interaction results in positive selection and survival signals which rescue DP thymocytes from death by neglect. Positive selection is critical for immune function, as this is the process by which a repertoire of T cells bearing useful TCR specificities is produce. However little is known about the transcriptional control of positive selection. We found that the transcription factor BCL11B controls early steps of positive selection, as removal results in attenuated TCR signaling and failure of positive selection. In addition, in the absence of BCL11B DP thymocytes have reduced survival even in the absence of TCR signaling, demonstrating that BCL11B is a major player in the control of survival of DP thymocytes. Supporting our hypothesis that BCL11B is critical for positive selection and survival of DP thymocytes we have evidence that BCL11B controls expression of genes associated with positive selection and survival of DP thymocytes. In addition, in the absence of BCL11B starting with DP stage of T cell development the reduced number of peripheral BCL11B-deficient T lymphocytes present an activated phenotype and mice develop wasting disease and colitis. Conditional removal of BCL11B in mature T cells also results in increased number of activated CD4+ T cells. These results support the hypothesis that BCL11B regulates mature CD4+ T lymphocytes. Using conditional and inducible mouse system and biochemical studies we propose to investigate the mechanisms by which BCL11B controls positive selection and survival of DP thymocytes through transcriptional control of gene expression. In addition we propose to determine the role of BCL11B in conventional and T regulatory CD4+ T cells. Public Health Relevance Statement: The results of these studies will contribute significantly to a molecular understanding of positive selection and survival of DP thymocytes, which both play a crucial role in generation of the appropriate T cells for an adequate immune response. In addition, these studies will contribute to understanding transcriptional program of effector CD4+ T and CD4+ T regulatory cells, and have important implications for autoimmune diseases.