Control of autoimmunity by follicular helper T cells and BCL6

描述（由申请方提供）：CD 4 T辅助细胞对于免疫应答的正确协调至关重要，并且对于帮助B细胞产生高亲和力抗原特异性抗体至关重要。滤泡辅助性T（Tfh）细胞是最近表征的CD 4 T细胞亚群，其作用是特异性地帮助B细胞产生抗体，部分通过促进生发中心反应。然而，Tfh细胞的发育失调可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CXCR 5。Tfh细胞的特征还在于转录阻遏物BCL 6的高表达和B细胞刺激性细胞因子IL-21的分泌。最近的数据表明，BCL 6是Tfh细胞的主要转录调节因子：强制BCL 6表达可以诱导T细胞中的Tfh表型，并且Tfh细胞在没有BCL 6的情况下不能发育。在这项提案中，我们试图利用BCL 6在Tfh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，由BCL 6促进的Tfh活性增加可以导致非特异性抗体应答并最终导致自身免疫，而BCL 6活性的阻断可以阻断Tfh功能，从而抑制自身免疫性疾病的进展。这一假设将在下文所述的具体目标中得到检验。这项研究将提供的信息是至关重要的Tfh细胞在疫苗开发中的操作。此外，这些实验可能会导致新的治疗自身免疫性疾病，如狼疮。 公共卫生相关性：CD 4 T辅助细胞对于免疫应答的适当协调至关重要，并且CD 4 T细胞在帮助B细胞制造对抗疾病的抗原特异性抗体方面特别重要。滤泡辅助性T（Tfh）细胞是最近发现的一种类型的CD 4 T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。本研究旨在通过一种新的系统来探讨Tfh细胞与自身免疫的关系，并使用一种新的药物来阻断Tfh的功能。这些研究可能会导致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.