Regulation of Follicular Helper T cell Differentiation and Vaccination by IL3

IL3 对滤泡辅助 T 细胞分化和疫苗接种的调节

• 批准号: 8853812
• 负责人: Alexander L Dent
• 金额: $ 7.8万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8853812
• 关键词: Affinity; Antibodies; Antibody Response; Antigens; Autoantibodies; Autoimmune Diseases; B-Lymphocytes; BCL6 gene; BLR1 gene; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Communicable Diseases; Development; Developmental Process; Gene Targeting; Helper-Inducer T-Lymphocyte; IL3 gene; Immune response; Interleukin-3; Knockout Mice; Lead; Modeling; Pathway interactions; Phenotype; Play; Production; Reaction; Regulation; Regulatory Pathway; Role; Structure of germinal center of lymph node; T cell differentiation; T-Lymphocyte; Testing; Transcription Repressor/Corepressor; Vaccination; chemokine receptor; cytokine; fighting; in vivo; insight; mouse model; novel; novel strategies; public health relevance; research study; vaccine development

DESCRIPTION (provided by applicant): T helper cells are critical for the proper function of the immune response and are essential for helping B cells make antibody. Follicular helper T (TFH) cells are a specialized subset of CD4+ T helper cells whose role is to help B cells produce high affinity antigen-specific antibody, and to promote the germinal center reaction. In the absence of TFH cells, germinal centers and secondary antibody responses cannot develop. However, excessive development of TFH cells is correlated with autoimmune disease. TFH cells are localized to germinal centers within B cell follicles due to their expression of the chemokine receptor CXCR5, and are further characterized by high expression of the transcription repressor BCL6 and the B cell stimulatory cytokine IL-21. Recent studies have shown that BCL6 is the master transcriptional regulator for TFH cells: forced BCL6 expression induces a TFH phenotype in T cells, and TFH cells cannot develop in the absence of BCL6. However, the mechanism for how BCL6 promotes the TFH phenotype is incompletely understood. Using a new BCL6 conditional knockout (cKO) mouse model, we have recently identified novel gene targets of BCL6 in CD4 T cells that are likely to play a role in TFH cell differentiation. In this proposal, we will seek to better define the role of a specific BCL6 target gene, IL-3. Our general hypothesis is that the novel BCL6 target gene IL-3 inhibits TFH function and that blocking IL-3 will increase the antibody response. This hypothesis will be tested in the proposal that follows. INNOVATION: We have identified a previously unknown regulatory pathway for how BCL6 controls TFH cell differentiation and will test this pathway functionally. We will investigate a novel strategy for increasing the efficacy of vaccination for the production of Ab. IMPACT: This study will provide insights into the unique developmental process of TFH cells, and will lead to the delineation of a new regulatory pathway that can be targeted to promote or inhibit TFH function. These experiments will provide information that is critical for understanding the development of the antibody response to fight infectious disease. These studies should aid in the development of vaccines that target TFH cells, and will also impact studies on autoantibody production.

描述（由申请人提供）：T 辅助细胞对于免疫反应的正常功能至关重要，并且对于帮助 B 细胞产生抗体至关重要。滤泡辅助T细胞（TFH）是CD4+ T辅助细胞的特殊亚群，其作用是帮助B细胞产生高亲和力的抗原特异性抗体，并促进生发中心反应。如果没有 TFH 细胞，生发中心和二抗反应就无法发展。然而，TFH 细胞的过度发育与自身免疫性疾病相关。 TFH 细胞由于表达趋化因子受体 CXCR5 而定位于 B 细胞滤泡内的生发中心，并进一步以转录抑制因子 BCL6 和 B 细胞刺激性细胞因子 IL-21 的高表达为特征。最近的研究表明，BCL6 是 TFH 细胞的主要转录调节因子：强制 BCL6 表达会诱导 T 细胞出现 TFH 表型，而 TFH 细胞在缺乏 BCL6 的情况下无法发育。然而，BCL6 如何促进 TFH 表型的机制尚不完全清楚。使用新的 BCL6 条件敲除 (cKO) 小鼠模型，我们最近在 CD4 T 细胞中发现了 BCL6 的新基因靶标，这些靶标可能在 TFH 细胞分化中发挥作用。在本提案中，我们将寻求更好地定义特定 BCL6 靶基因 IL-3 的作用。我们的一般假设是，新的 BCL6 靶基因 IL-3 抑制 TFH 功能，并且阻断 IL-3 将增加抗体反应。该假设将在随后的提案中得到检验。创新：我们已经确定了 BCL6 如何控制 TFH 细胞分化的一条先前未知的调控途径，并将对该途径进行功能测试。我们将研究一种提高抗体生产疫苗接种效率的新策略。影响：这项研究将深入了解 TFH 细胞的独特发育过程，并将导致描绘出一种新的调控途径，该途径可以有针对性地促进或抑制 TFH 功能。这些实验将为了解对抗传染病的抗体反应的发展提供至关重要的信息。这些研究应该有助于开发针对 TFH 细胞的疫苗，并且还将影响自身抗体生产的研究。