Molecular regulation of T follicular helper cell maintenance by Bach2 and RankL

滤泡辅助性T细胞（TFH）是在生发中心（GC）反应期间为B细胞提供帮助的CD 4 + T细胞亚群。没有TFH细胞，B细胞不能分化成高亲和力记忆B细胞或产生抗体的浆细胞。高亲和力抗体有效地保护身体免受病原体的侵害，但如果它们针对自身或无害的环境抗原，也可能导致自身免疫或过敏。因此，了解TFH细胞的分子调控机制具有重要的临床意义。尽管从初始T细胞产生TFH细胞的早期信号现在已经很好地理解，但是对于来自B细胞或可能还有在GC应答期间维持TFH表型的基质细胞的因子知之甚少。这个晚期阶段是治疗干预的决定性阶段，无论是促进还是抑制抗体responses.In一个新的因素，是差异表达的TFH与非TFH效应细胞在晚期阶段的GC responses.In屏幕，我们确定了转录因子Bach 2和TNF超家族成员的秩配体（RankL）作为新的球员。Bach 2主要以其在浆细胞分化中的重要作用而闻名。RankL在T细胞与树突状细胞（DC）的早期相互作用中起作用，导致其活化和产生炎性细胞因子。这两个因素都没有与TFH cells的控制before. Using体内T/B相互作用的小鼠模型，它允许研究和操纵抗原特异性TFH细胞的发展，我们已经表明，TFH细胞需要低表达的转录抑制因子Bach 2上调RankL在晚期阶段的GC反应。Bach2在已经分化的TFH细胞中的异位过表达导致RankL下调，随后TFH细胞消失。基于我们的初步数据，我们提出了以下模型，Bach 2和RankL如何作用于TFH细胞以在GC反应的晚期稳定其表型：1）Bach2在TFH细胞中必须处于低水平以允许RankL表达。2）表达RankL的TFH细胞与GC中的Rank阳性基质细胞或DC相互作用。3）Rank交联诱导这些细胞产生IL-6。4）IL-6通过诱导自分泌IL-6稳定TFH细胞表型。21生产。在这个提议中，我们希望实验性地解决上述模型的单个步骤。特别是，我们想回答以下问题：I）Bach 2如何在晚期GC反应中调节TFH细胞？II）TFH细胞如何通过RankL/Rank与GC中的基质细胞/DC相互作用？III）GC中的基质细胞/DC如何维持TFH细胞？这些实验不仅将揭示Bach 2-RankL轴调节TFH细胞的分子机制，而且还将首次证明TFH/基质细胞相互作用直接在GC中的重要性。

T follicular helper (TFH) cells are the subpopulation of CD4+ T cells providing help for B cells during the germinal center (GC) response. Without TFH cells, B cells cannot differentiate into high affinity memory B cells or antibody producing plasma cells. High affinity antibodies effectively protect the body from pathogens but can also cause autoimmunity or allergies if they are directed against self or harmless environmental antigens. Therefore, it is of high clinical importance to understand the molecular mechanisms regulating TFH cells. Whereas the early signals to generate TFH cells from naive T cells are now well understood, very little is known about factors from B cells or probably also stromal cells maintaining the TFH phenotype during the GC response. This late phase is the decisive stage for therapeutic intervention to either promote or dampen antibody responses.In a screen for novel factors that are differentially expressed by TFH versus non-TFH effector cells in late phases of the GC response, we identified the transcription factor Bach2 and the TNF superfamily member Rank-Ligand (RankL) as new players. Bach2 is mainly known for its important role in plasma cell differentiation. RankL plays a role in the early interaction of T cells with dendritic cells (DC) leading to their activation and production of inflammatory cytokines. Both factors have not been associated with the control of TFH cells before.Using an in vivo T/B interaction mouse model which allows to study and manipulate the development of antigen-specific TFH cells, we have shown that TFH cells require low expression of the transcriptional repressor Bach2 to upregulate RankL in late phases of the GC reaction. Ectopic overexpression of Bach2 in already differentiated TFH cells results in RankL downregulation and subsequently disappearance of TFH cells. On the contrary, Bach2 knock-out mice show an exaggerated TFH response.Based on our preliminary data we propose the following model, how Bach2 and RankL act on TFH cells to stabilize their phenotype in late phases of the GC response:1) Bach2 has to be at low levels in TFH cells to allow RankL expression.2) RankL-expressing TFH cells interact with Rank-positive stromal cells or DC in the GC.3) Rank crosslinking induces production of IL-6 by these cells.4) IL-6 stabilizes the TFH cell phenotype by inducing autocrine IL-21 production.With this proposal we want to experimentally address the single steps of the above model. In particular, we want to answer the following questions:I) How does Bach2 regulate TFH cells in the late GC reaction?II) How do TFH cells interact with stromal cells / DC in the GC via RankL / Rank?III) How do stromal cells / DC in the GC maintain TFH cells?These experiments will not only reveal the molecular mechanisms of the Bach2 - RankL axis for regulation of TFH cells but will also for the first time demonstrate the importance of TFH / stromal cell interactions directly in the GC.