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

描述（由申请方提供）：双阳性胸腺细胞的命运取决于皮质胸腺上皮细胞上呈递的TCR和自身肽-MHC复合物之间相互作用的强度和持续时间。弱相互作用导致正选择和存活信号，其将DP胸腺细胞从忽视死亡中拯救出来。正选择对于免疫功能是至关重要的，因为这是产生具有有用的TCR特异性的T细胞库的过程。然而，很少有人知道的转录控制的积极选择。我们发现转录因子BCL 11B控制正选择的早期步骤，因为去除导致TCR信号传导减弱和正选择失败。此外，在不存在BCL 11B的情况下，DP胸腺细胞即使在不存在TCR信号传导的情况下也具有降低的存活率，表明BCL 11B是控制DP胸腺细胞存活的主要参与者。支持我们的假设，BCL 11 B是DP胸腺细胞的阳性选择和生存的关键，我们有证据表明，BCL 11 B控制与阳性选择和DP胸腺细胞的生存相关的基因的表达。此外，在从T细胞发育的DP阶段开始不存在BCL 11B的情况下，外周BCL 11B缺陷型T淋巴细胞的数量减少，呈现活化的表型，并且小鼠发展为消耗性疾病和结肠炎。在成熟T细胞中有条件地去除BCL 11B也导致活化的CD 4 + T细胞的数量增加。这些结果支持BCL 11B调节成熟的CD 4 + T淋巴细胞的假设。使用条件和诱导小鼠系统和生化研究，我们建议调查的机制，BCL 11 B控制阳性选择和DP胸腺细胞的生存通过转录控制基因表达。此外，我们建议确定BCL 11 B在常规和T调节性CD 4 + T细胞中的作用。公共卫生相关性声明：这些研究的结果将有助于显着的DP胸腺细胞，这两者都发挥了至关重要的作用，在产生适当的T细胞，充分的免疫反应的积极选择和生存的分子理解。此外，这些研究将有助于理解效应性CD 4 + T细胞和CD 4 + 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.