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.
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