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

Bach2 和 RankL 对滤泡辅助 T 细胞维持的分子调节

基本信息

批准号：
325487863
负责人：
Professor Dr. Andreas Hutloff
金额：
--
依托单位：
Institut für Immunologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/325487863?language=en
关键词：
Molecular regulation follicular helper cell

项目摘要

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.

T滤泡辅助细胞（TFH）是CD4+ T细胞的亚群，在生发中心（GC）反应中为B细胞提供帮助。没有TFH细胞，B细胞不能分化为高亲和记忆B细胞或产生抗体的浆细胞。高亲和力抗体有效地保护机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，也会引起自身免疫或过敏。因此，了解TFH细胞的分子调控机制具有重要的临床意义。虽然现在已经很好地理解了幼稚T细胞产生TFH细胞的早期信号，但对于B细胞或基质细胞在GC反应期间维持TFH表型的因子知之甚少。这一后期阶段是促进或抑制抗体反应的治疗干预的决定性阶段。在筛选TFH与非TFH效应细胞在GC反应后期差异表达的新因子时，我们确定了转录因子Bach2和TNF超家族成员rank -配体（RankL）作为新参与者。Bach2主要因其在浆细胞分化中的重要作用而为人所知。RankL在T细胞与树突状细胞（DC）的早期相互作用中起作用，导致它们的激活和炎症细胞因子的产生。这两个因素之前都没有与TFH细胞的控制相关。利用体内T/B相互作用小鼠模型，研究和操纵抗原特异性TFH细胞的发育，我们发现TFH细胞在GC反应后期需要低表达转录抑制因子Bach2来上调RankL。在已经分化的TFH细胞中，Bach2的异位过表达会导致RankL下调，进而导致TFH细胞消失。相反，Bach2敲除小鼠表现出夸张的TFH反应。根据我们的初步数据，我们提出了以下模型，说明Bach2和RankL如何作用于TFH细胞以稳定GC反应后期的表型：1)TFH细胞中Bach2必须处于低水平才能允许RankL的表达。2)表达rankl的TFH细胞与gc中Rank阳性的基质细胞或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-21的产生来稳定TFH细胞表型。有了这个建议，我们想通过实验解决上述模型的单个步骤。我们特别想回答以下问题：1)在GC反应后期，Bach2是如何调控TFH细胞的？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Bach2 - RankL轴调控TFH细胞的分子机制，而且将首次证明TFH /基质细胞直接相互作用在GC中的重要性。