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

BCL11B 转录因子对 CD4 T 细胞发育和功能的调节

• 批准号: 7760538
• 负责人: Dorina Avram
• 金额: $ 23.46万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760538
• 关键词: Attenuated; Autoimmune Diseases; Biochemical; CD4 Positive T Lymphocytes; Cessation of life; Colitis; Excision; Failure; Gene Expression; Generations; Immune response; Mature T-Lymphocyte; Molecular; Mus; Names; Peptide/MHC Complex; Peripheral; Phenotype; Play; Principal Investigator; Process; Regulation; Regulatory T-Lymphocyte; Research; Role; Signal Transduction; Specificity; Staging; Stream; System; T-Cell Development; T-Lymphocyte; Thymic epithelial cell; Transcriptional Regulation; Wasting Syndrome; immune function; neglect; programs; public health relevance; thymocyte; transcription factor

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.

描述（由申请人提供）：双胸腺细胞的命运取决于TCR和自肽MHC复合物之间相互作用的强度和持续时间，呈现在皮质胸腺上皮细胞上。相互作用较弱会导致阳性选择和生存信号，从而从忽视中挽救了DP胸腺细胞。阳性选择对于免疫功能至关重要，因为这是产生具有有用TCR特异性的T细胞库的过程。然而，关于阳性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信号传导和阳性选择的失败。此外，在没有BCL11b DP胸腺细胞的情况下，即使没有TCR信号传导，胸腺细胞也降低了存活率，这表明BCL11B是控制DP胸腺细胞存活的主要参与者。支持我们的假设，即Bcl11b对于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胸腺细胞阳性选择和存活相关的基因的表达。此外，在没有BCL11b的情况下，从T细胞发育的DP阶段开始，外周BCl11b缺乏的T淋巴细胞的数量减少了活化的表型，而小鼠会发展出浪费疾病和结肠炎。成熟T细胞中BCL11b的有条件去除也导致活化的CD4+ T细胞数量增加。这些结果支持BCL11b调节成熟CD4+ T淋巴细胞的假设。使用条件和可诱导的小鼠系统以及生化研究，我们建议研究BCL11b通过基因表达的转录控制DP胸腺细胞的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CD4+ T细胞中的作用。公共卫生相关性陈述：这些研究的结果将有助于对DP胸腺细胞的阳性选择和存活的分子理解，这两者在适当的T细胞的产生中起着至关重要的作用，以实现适当的免疫反应。此外，这些研究将有助于理解效应子CD4+ T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。