Control of autoimmunity by follicular helper T cells and BCL6

滤泡辅助 T 细胞和 BCL6 控制自身免疫

• 批准号: 8072744
• 负责人: Alexander L Dent
• 金额: $ 22.87万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8072744
• 关键词: Affinity; Antibodies; Antibody Formation; Antigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; BCL6 gene; BLR1 gene; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Data; Development; Disease; Disease Progression; Dose; Helper-Inducer T-Lymphocyte; Immune response; Immunity; Lead; Link; Lupus; Pathologic; Peptides; Pharmaceutical Preparations; Phenotype; Reaction; Role; Structure of germinal center of lymph node; System; T-Lymphocyte; Testing; Transcription Repressor/Corepressor; chemokine receptor; cytokine; fighting; in vitro activity; in vivo; inhibitor/antagonist; mouse model; novel; public health relevance; research study; response; small molecule; vaccine development

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.

描述（由申请人提供）：CD4 T 辅助细胞对于免疫反应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 T (Tfh) 细胞是最近鉴定的 CD4 T 细胞亚群，其作用是专门帮助 B 细胞产生抗体，部分是通过促进生发中心反应。然而，Tfh 细胞发育失调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 细胞的另一个特点是高表达转录抑制因子 BCL6，并分泌 B 细胞刺激性细胞因子 IL-21。最近的数据表明，BCL6是Tfh细胞的主要转录调节因子：强制BCL6表达可以诱导T细胞中的Tfh表型，并且在没有BCL6的情况下Tfh细胞无法发育。在本提案中，我们寻求利用 BCL6 在 Tfh 发育和功能中的核心作用，以更好地了解 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并最终导致自身免疫，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。该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，这些实验可能会带来针对狼疮等自身免疫性疾病的新疗法。 公共卫生相关性：CD4 T 辅助细胞对于免疫反应的正确协调至关重要，CD4 T 细胞在帮助 B 细胞制造抗击疾病的抗原特异性抗体方面尤其重要。滤泡辅助性 T (Tfh) 细胞是最近发现的一种 CD4 T 细胞，其作用专门帮助 B 细胞产生抗体。然而，Tfh 细胞也会促进自身免疫性疾病。在这里，我们想利用一种新的系统来探讨Tfh细胞与自身免疫之间的关系，并使用一种新的药物来阻断Tfh功能。这些研究可能会带来治疗自身免疫性疾病的新疗法。