T follicular helper (Tfh) cells are a specialized T cell subset that regulates the long-lived production of highly specific Abs by B cells during the germinal center (GC) reaction. However, the transcriptional network sustaining the Tfh cell phenotype and function is still incompletely understood. In this study, we identify the transcription factor Bach2 as a central negative regulator of Tfh cells. Ectopic overexpression of Bach2 in murine Tfh cells resulted in a rapid loss of their phenotype and subsequent breakdown of the GC response. Low Bach2 expression levels are required to maintain high expression of the signature cytokine IL-21, the coinhibitory receptor TIGIT and the transcriptional repressor Bcl-6. In stark contrast to the regulatory network in GC B cells, Bach2 in Tfh cells is not coexpressed with Bcl-6 at high levels to inhibit the antagonizing factor Blimp-1, but suppresses Bcl-6 by direct binding to the promoter. These data reveal that by replacing an activating complex of Batf and Irf-4 at the Bcl-6 promoter, Bach2 regulates the transcriptional network of Tfh cells in a different way, as in GC B cells.

Background Vitamin A regulates the adaptive immune response and a modulatory impact on type I allergy is discussed. The cellular mechanisms are largely unknown. Objective To determine the vitamin A‐responding specific lymphocyte reaction in vivo. Methods Antigen‐specific B and T lymphocytes were analyzed in an adoptive transfer airway inflammation mouse model in response to 9‐cis retinoic acid (9cRA) and after lymphocyte‐specific genetic targeting of the receptor RARα. Flow cytometry, quantitative PCR, next‐generation sequencing, and specific Ig‐ELISA were used to characterize the cells functionally. Results Systemic 9cRA profoundly enhanced the specific IgA‐secreting B‐cell frequencies in the lung tissue and serum IgA while reducing serum IgE concentrations. RARα overexpression in antigen‐specific B cells promoted differentiation into plasmablasts at the expense of germinal center B cells. In antigen‐specific T cells, RARα strongly promoted the differentiation of T follicular helper cells followed by an enhanced germinal center response. Conclusions 9cRA signaling via RARα impacts the allergen‐specific immunoglobulin response directly by the differentiation of B cells and indirectly by promoting T follicular helper cells.