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辅助细胞对免疫反应的正常功能至关重要，对帮助B细胞产生抗体至关重要。滤泡辅助T细胞（Follicular helper T， TFH）是CD4+ T辅助细胞的一个特殊亚群，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。在缺乏TFH细胞的情况下，生发中心和二抗反应不能发展。然而，TFH细胞的过度发育与自身免疫性疾病相关。TFH细胞由于其趋化因子受体CXCR5的表达而定位于B细胞卵泡内的生发中心，并进一步以高表达转录抑制因子BCL6和B细胞刺激因子IL-21为特征。最近的研究表明，BCL6是TFH细胞的主要转录调节因子：在T细胞中，BCL6的强制表达会诱导TFH表型，而在缺乏BCL6的情况下，TFH细胞无法发育。然而，BCL6促进TFH表型的机制尚不完全清楚。利用一种新的BCL6条件敲除（cKO）小鼠模型，我们最近在CD4 T细胞中发现了BCL6的新基因靶点，这些靶点可能在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，阻断IL-3会增加抗体反应。这一假设将在接下来的提议中得到验证。创新：我们已经确定了一个以前未知的BCL6如何控制TFH细胞分化的调控途径，并将对该途径进行功能测试。我们将研究一种新的策略来提高疫苗接种对Ab产生的效力。影响：本研究将提供对TFH细胞独特发育过程的见解，并将导致描绘一个新的调控途径，可以靶向促进或抑制TFH功能。这些实验将为了解抗体反应的发展提供至关重要的信息，以对抗传染病。这些研究应该有助于开发针对TFH细胞的疫苗，也将影响自身抗体生产的研究。