Regulation of Follicular Helper T cell Differentiation and Vaccination by IL3

描述（由申请方提供）：T辅助细胞对于免疫应答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。滤泡辅助性T（TFH）细胞是CD 4+辅助性T细胞的一个特化亚群，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，生发中心和二次抗体反应不能发展。然而，TFH细胞的过度发育与自身免疫性疾病相关。TFH细胞由于其表达趋化因子受体CXCR 5而定位于B细胞滤泡内的生发中心，并且进一步特征在于高表达转录阻遏物BCL 6和B细胞刺激性细胞因子IL-21。最近的研究表明，BCL 6是TFH细胞的主要转录调节因子：强迫BCL 6表达诱导T细胞中的TFH表型，并且TFH细胞在BCL 6不存在的情况下不能发育。然而，BCL 6如何促进TFH表型的机制尚未完全了解。使用一种新的BCL 6条件性敲除（cKO）小鼠模型，我们最近确定了新的基因靶BCL 6在CD 4 T细胞可能发挥作用的TFH细胞分化。在这项提案中，我们将寻求更好地定义特定BCL 6靶基因IL-3的作用。我们的一般假设是新的BCL 6靶基因IL-3抑制TFH功能，并且阻断IL-3将增加抗体应答。这一假设将在下文的提案中得到检验。创新：我们已经确定了一个以前未知的调控途径，BCL 6如何控制TFH细胞分化，并将测试这一途径的功能。我们将研究一种新的策略，以提高疫苗接种的效力，以产生抗体。影响：这项研究将为TFH细胞独特的发育过程提供见解，并将导致一个新的调控途径，可以有针对性地促进或抑制TFH功能的划定。这些实验将提供信息，这是了解抗体反应的发展，以打击传染病的关键。这些研究应该有助于开发靶向TFH细胞的疫苗，也将影响自身抗体产生的研究。

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.