Role of BCL11B in CD4+ T Cells

描述（由申请人提供）：T细胞发育、CD 4 + T细胞活化和效应子功能的转录控制的许多方面，以及它们与疾病状态如自身免疫、炎症和过敏的关系仍有待揭示。我们的初步研究结果表明，新的转录因子BCL 11 B起着关键作用的双阳性（DP）阶段的T细胞发育的积极选择，也控制DP胸腺细胞的生存/凋亡。因此，在目的1中，我们提出研究BCL 11 B在双阳性胸腺细胞发育为单阳性胸腺细胞中的作用，特别是在阳性选择过程中。对于这些研究，我们将有条件地去除BCL 11B开始DP胸腺细胞，我们将调查积极的选择在体内和体外，以及BCL 11B控制的过程的生化机制。在目标2中，我们建议研究BCL 11 B在T细胞发育的DP阶段控制程序性细胞死亡中的作用，以及BCL 11 B控制这一过程的机制。BCL 11B也存在于成熟的CD 4 + T细胞中，包括Th 1和Th 2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BCL 11 B在控制成熟CD 4 + T细胞功能中的作用。通过这一目标下的研究，我们将具体评估BCL 11 B在CD 4 + T细胞活化和Th 1/Th 2细胞极化中的作用。此外，我们将研究BCL 11 B在成熟CD 4 + T淋巴细胞存活和增殖中的作用。此外，我们将调查的NuRD复合物的含义，以及辅激活因子复合物的成分，在BCL 11 B转录控制的调解。此外，我们将调查的调制BCL 11 B的转录调节功能的磷酸化反应T细胞活化。这些研究的成功完成将阐明BCL 11B在β选择后以及在成熟CD 4 + 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CD 4 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.