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

描述(申请人提供)：双阳性胸腺细胞的命运由胸腺皮质上皮细胞上的TCR和自体多肽-MHC复合体相互作用的强度和持续时间决定。弱的相互作用导致积极的选择和生存信号，通过忽视将DP胸腺细胞从死亡中拯救出来。阳性选择对免疫功能至关重要，因为这是产生具有有用的TCR特异性的T细胞的过程。然而，人们对正选择的转录调控知之甚少。我们发现转录因子BCL11B控制着正选择的早期步骤，因为去除BCL11B会导致TCR信号减弱和正选择失败。此外，在缺乏BCL11B的情况下，即使在没有TCR信号的情况下，DP胸腺细胞的存活率也会降低，这表明BCL11B是控制DP胸腺细胞存活的主要因素。支持我们的假设，即BCL11B对阳性选择和DP胸腺细胞的存活至关重要，我们有证据表明BCL11B控制着与阳性选择和DP胸腺细胞存活相关的基因的表达。此外，在缺乏BCL11B的情况下，从T细胞发育的DP阶段开始，外周血中缺乏BCL11B的T淋巴细胞数量减少，呈现激活的表型，小鼠出现衰减性疾病和结肠炎。有条件地去除成熟T细胞中的BCL11B也会导致激活的CD4T细胞数量增加。这些结果支持BCL11B调节成熟的CD4T淋巴细胞的假设。利用条件性和可诱导性小鼠系统和生化研究，我们建议研究BCL11B通过转录控制基因表达来控制阳性选择和DP胸腺细胞存活的机制。此外，我们建议确定BCL11B在常规和T调节的CD4T细胞中的作用。公共卫生相关声明：这些研究的结果将大大有助于从分子上理解阳性选择和DP胸腺细胞的存活，这两者在产生适当的T细胞以进行充分的免疫反应方面都起着至关重要的作用。此外，这些研究将有助于了解效应器CD4T和CD4T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.