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: 8681872
• 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/8681872
• 关键词: Affinity; Antibodies; Antibody Formation; 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适当功能至关重要，对于帮助B细胞生成抗体至关重要。卵泡辅助T（TFH）细胞是CD4+ T辅助细胞的专门子集，其作用是帮助B细胞产生高亲和力抗原特异性抗体，并促进生发中心反应。在没有TFH细胞的情况下，生发中心和二抗反应无法发展。但是，TFH细胞的过度发育与自身免疫性疾病有关。 TFH细胞由于趋化因子受体CXCR5的表达而定位于B细胞卵泡内的生发中心，进一步的特征是转录抑制剂BCl6和B细胞刺激性细胞因子IL-21的高表达。最近的研究表明，BCL6是TFH细胞的主要转录调节剂：强迫BCL6表达诱导T细胞中的TFH表型，而在没有BCL6的情况下，TFH细胞无法发展。但是，尚不完全了解BCL6如何促进TFH表型的机制。使用新的BCL6条件敲除（CKO）小鼠模型，我们最近确定了CD4 T细胞中BCl6的新基因靶标，这些基因可能在TFH细胞分化中起作用。在此提案中，我们将寻求更好地定义特定的Bcl6靶基因IL-3的作用。我们的一般假设是，新型的Bcl6靶基因IL-3抑制了TFH功能，而阻断IL-3会增加抗体反应。该假设将在随后的提案中进行检验。创新：我们已经确定了BCl6如何控制TFH细胞分化的先前未知的调节途径，并将在功能上测试该途径。我们将研究一种新的策略，以提高疫苗接种对AB的生产的疗效。影响：这项研究将为TFH细胞的独特发育过程提供见解，并将导致划定一种新的调节途径，该途径可以针对促进或抑制TFH功能。这些实验将提供有关理解对抗传染病的抗体反应发展至关重要的信息。这些研究应有助于开发针对TFH细胞的疫苗，还将影响对自身抗体生产的研究。