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

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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.