Control of autoimmunity by follicular helper T cells and BCL6

描述（由申请人提供）：CD4 T辅助细胞对免疫反应的适当协调至关重要，对帮助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细胞（Tfh）是CD4 T细胞的一个新亚型，其作用是通过促进生发中心反应来帮助B细胞产生抗体。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的特征。最近的研究表明，BCL6是Tfh细胞的主要转录调控因子：强制BCL6的表达可以诱导T细胞的Tfh表型，而在缺乏BCL6的情况下Tfh细胞无法发育。在本研究中，我们试图利用BCL6在Tfh发育和功能中的核心作用来更好地理解Tfh细胞与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。这一假设将在下面描述的具体目标中得到检验。这项研究将为疫苗开发中Tfh细胞的操作提供至关重要的信息。此外，这些实验可能会导致红斑狼疮等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.