Control of autoimmunity by follicular helper T cells and BCL6

描述(由申请人提供)：CD4T辅助细胞对免疫反应的正确协调至关重要，并且对于帮助B细胞制造高亲和力的抗原特异性抗体至关重要。滤泡辅助性T细胞(TFH)是最近鉴定的CD4T细胞亚群，其作用是帮助B细胞产生抗体，部分是通过促进生发中心反应。然而，TFH细胞的不受调控的发育可能导致自身免疫性疾病。TFH细胞定位于B细胞滤泡，因此表达趋化因子受体CXCR5。TFH细胞还具有高表达转录抑制因子BCL6和分泌B细胞刺激因子IL-21的特点。最近的数据表明，BCL6是TFH细胞的主要转录调控因子：强迫表达BCL6可以诱导T细胞中的TFH表型，而TFH细胞在没有BCL6的情况下不能发育。在这项建议中，我们试图利用BCL6在TFH的发育和功能中的核心作用，以更好地了解TFH细胞和自身免疫之间的联系。我们的假设是，BCL6促进的TFH活性增加可以导致非特异性抗体反应，最终导致自身免疫，而阻断BCL6活性可以阻断TFH功能，从而抑制自身免疫性疾病的进展。这一假设将在下文描述的具体目标中得到检验。这项研究将提供对疫苗开发中TFH细胞的操纵至关重要的信息。此外，这些实验可能为狼疮等自身免疫性疾病带来新的治疗方法。 公共卫生相关性：CD4T辅助细胞对免疫反应的正确协调至关重要，而CD4T细胞在帮助B细胞制造抗病抗原特异性抗体方面尤为重要。滤泡辅助性T细胞(TFH)是最近发现的一种CD4T细胞，其作用是特异性地帮助B细胞产生抗体。然而，TFH细胞也可以促进自身免疫性疾病。在这里，我们想用一种新的系统来探索TFH细胞与自身免疫的关系，并用一种新的药物来阻断TFH的功能。这些研究可能会带来治疗自身免疫性疾病的新疗法。

DESCRIPTION (provided by applicant): CD4 T helper cells are critical for the proper orchestration of the immune response and are essential for helping B cells make high affinity antigen-specific antibody. Follicular helper T (Tfh) cells are a recently characterized subset of CD4 T cells whose role is specifically to help B cells produce antibody, in part by promoting the germinal center reaction. However, deregulated development of Tfh cells can lead to autoimmune disease. Tfh cells are localized to B cell follicles and thus express the chemokine receptor CXCR5. Tfh cells are also characterized by high expression of the transcription repressor BCL6, and secretion of the B cell stimulatory cytokine IL-21. Recent data indicates that BCL6 is the master transcriptional regulator for Tfh cells: forced BCL6 expression can induce the Tfh phenotype in T cells, and Tfh cells cannot develop in the absence of BCL6. In this proposal, we seek to take advantage of the central role for BCL6 in Tfh development and function to better understand the link between Tfh cells and auto-immunity. Our hypothesis is that increased Tfh activity promoted by BCL6 can lead to non-specific antibody responses and eventually to autoimmunity, while blockade of BCL6 activity can block Tfh function and thus inhibit autoimmune disease progression. This hypothesis will be tested in the specific aims described below. This study will provide information that is critical for the manipulation of Tfh cells in vaccine development. Further, these experiments may lead to novel treatments for autoimmune diseases such as lupus. PUBLIC HEALTH RELEVANCE: CD4 T helper cells are critical for the proper orchestration of the immune response, and CD4 T cells are particularly important in helping B cells in make antigen-specific antibody that fights disease. Follicular helper T (Tfh) cells are a recently discovered type of CD4 T cells whose role is specifically to help B cells produce antibody. However, Tfh cells can also promote autoimmune disease. Here we want to probe the relationship between Tfh cells and autoimmunity using a novel system, and also use a novel drug to block Tfh function. These studies may lead to new therapies for the treatment of autoimmune disease.