Role of BCL11B in CD4+ T Cells

描述(申请人提供)：T细胞发育、CD4+T细胞激活和效应器功能的转录控制的许多方面，以及它们与疾病状态的关系，如自身免疫、炎症和过敏，仍未被发现。我们的初步结果表明，新的转录因子BCL11B在双阳性(DP)T细胞发育的阳性选择中起着关键作用，并控制双阳性胸腺细胞的存活/凋亡。因此，在目标1中，我们建议研究BCL11B在胸腺细胞从双阳性到单阳性的发育过程中的作用，特别是在阳性选择过程中。在这些研究中，我们将从DP胸腺细胞开始，有条件地去除BCL11B，我们将研究体内和体外的正选择，以及BCL11B控制这一过程的生化机制。在目标2中，我们建议研究BCL11B在控制T细胞发育的DP阶段的程序性细胞死亡中的作用以及BCL11B控制这一过程的机制。BCL11B也存在于成熟的CD4+T细胞中，包括Th1和Th2效应细胞，并调节IL-2和几种细胞因子和细胞因子受体的表达。因此，在目标3中，我们建议研究BCL11B在控制成熟的CD4+T细胞功能中的作用。通过这一目标下的研究，我们将专门评估BCL11B在CD4+T细胞活化和Th1/Th2细胞极化中的作用。此外，我们还将研究BCL11B在成熟的CD4+T淋巴细胞存活和增殖中的作用。此外，我们还将研究NuRD复合体以及辅活化子复合体的成分在BCL11B转录调控中的作用。此外，我们还将研究T细胞激活时磷酸化对BCL11B转录调节功能的调节作用。这些研究的成功完成将阐明BCL11B在β选择后的作用，以及在成熟的CD4+T淋巴细胞中的作用。此外，这些研究将加深我们对T细胞发育后期和成熟的CD4T细胞功能转录调控的理解，并对自身免疫性疾病具有重要意义。

DESCRIPTION (provided by applicant): Many aspects of transcriptional control of T cell development, CD4+ T cell activation and effector function, as well as their relation to disease states, such as autoimmunity, inflammation and allergy remain to be uncovered. Our preliminary results demonstrate that the novel transcription factor BCL11B plays a critical role at the double positive (DP) stage of T cell development in positive selection, and also controls survival/apoptosis of DP thymocytes. Therefore in Aim 1 we propose to investigate the role of BCL11B in the development from double positive to single positive thymocytes, specifically in the process of positive selection. For these studies we will conditionally remove BCL11B starting with DP thymocytes and we will investigate positive selection both in vivo and in vitro, as well as the biochemical mechanisms by which BCL11B controls the process. In aim 2 we propose to investigate the role of BCL11B in the control of programmed cell death at the DP stage of T cell development and the mechanisms by which BCL11B controls this process. BCL11B is also present also in mature CD4+ T cells, including Th1 and Th2 effector cells, and regulates expression of interleukin-2 and several cytokines and cytokine receptors. Therefore in aim 3 we propose to study the role of BCL11B in the control of mature CD4+ T cell function. Through the studies under this aim, we will specifically assess the role of BCL11B in CD4 + T cell activation and in Th1/Th2 cell polarization. In addition, we will investigate the role of BCL11B in survival and proliferation of mature CD4+ T lymphocytes. Additionally, we will investigate the implication of the NuRD complex, as well as of components of the coactivator complex, in the mediation of BCL11B transcriptional control. Moreover, we will investigate the modulation of BCL11B transcriptional regulatory function by phosphorylation in response to T cell activation. Successful completion of these studies will elucidate the role of BCL11B after beta selection, as well as in mature CD4+ T lymphocytes. In addition, these studies will enhance our understanding of the transcriptional control of late stages of T cell development and mature CD4 T cell function, and have important implications for autoimmune diseases.