Role of BCL11B in CD4+ T Cells

描述（由申请人提供）：T细胞发育、CD4+ T细胞活化和效应功能的转录控制的许多方面，以及它们与自身免疫、炎症和过敏等疾病状态的关系仍有待发现。我们的初步研究结果表明，新的转录因子BCL11B在T细胞发育的双阳性（DP）阶段发挥了积极选择的关键作用，并控制DP胸腺细胞的存活/凋亡。因此，在Aim 1中，我们拟研究BCL11B在胸腺细胞从双阳性向单阳性发育过程中的作用，特别是在阳性选择过程中的作用。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阳性选择，以及BCL11B控制这一过程的生化机制。在目的2中，我们建议研究BCL11B在T细胞发育DP阶段控制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，并调节白细胞介素-2和几种细胞因子和细胞因子受体的表达。因此，在目的3中，我们提出研究BCL11B在控制成熟CD4+ T细胞功能中的作用。通过这一目的下的研究，我们将具体评估BCL11B在CD4 + T细胞活化和Th1/Th2细胞极化中的作用。此外，我们将研究BCL11B在成熟CD4+ T淋巴细胞存活和增殖中的作用。此外，我们将研究NuRD复合体以及辅激活子复合体的组分在BCL11B转录控制中的作用。此外，我们将研究BCL11B在T细胞激活时通过磷酸化调节转录调节功能。这些研究的成功完成将阐明BCL11B在β选择后以及在成熟CD4+ T淋巴细胞中的作用。此外，这些研究将增强我们对T细胞发育晚期和成熟CD4 T细胞功能的转录控制的理解，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.