Regulation of Follicular Helper T cell Differentiation and Vaccination by IL3

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，也是帮助B细胞制造抗体的关键。滤泡辅助T细胞(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。在没有TFH细胞的情况下，生发中心和二次抗体反应不能形成。然而，TFH细胞的过度发育与自身免疫性疾病有关。由于趋化因子受体CXCR5的表达，TFH细胞定位于B细胞滤泡内的生发中心，并进一步具有转录抑制因子BCL6和B细胞刺激因子IL-21的高表达。最近的研究表明，BCL6是TFH细胞的主要转录调控因子：强迫表达BCL6会诱导T细胞产生TFH表型，而TFH细胞在没有BCL6的情况下无法发育。然而，BCL6如何促进TFH表型的机制还不完全清楚。利用一种新的BCL6条件性基因敲除(CKO)小鼠模型，我们最近在CD4T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。在这项提案中，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，新的BCL6靶基因IL-3抑制TFH功能，阻断IL-3将增强抗体反应。这一假设将在接下来的提案中得到检验。创新：我们已经确定了BCL6如何控制TFH细胞分化的先前未知的调控途径，并将从功能上测试这一途径。我们将研究一种新的策略，以提高疫苗接种的效力，以生产抗体。影响：这项研究将为TFH细胞独特的发育过程提供洞察力，并将导致描绘一条新的调控途径，可以有针对性地促进或抑制TFH功能。这些实验将提供对理解抗体反应的发展以对抗传染病至关重要的信息。这些研究应该有助于针对TFH细胞的疫苗的开发，也将影响对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.