Follicular regulatory T (Tfr) cells have specialized roles in modulating Tfh help to B cells. However, the precise role of Tfr cells in controlling antibody responses to foreign and autoantigens in vivo is still unclear due to a lack of specific tools. We developed a Tfr-deleter mouse that selectively deletes Tfr cells, facilitating temporal studies. We found Tfr cells regulate early, but not late, germinal center (GC) responses to control antigen-specific antibody and B cell memory. Deletion of Tfr cells also resulted in increased self-reactive IgG and IgE. The increased IgE levels led us to interrogate the role of Tfr cells in house dust mite (HDM) models. We found Tfr cells control Tfh13 cell-induced IgE. In vivo, loss of Tfr cells increased HDM-specific IgE and lung inflammation. Thus, Tfr cells control IgG and IgE responses to vaccines, allergens and autoantigens and exert critical immunoregulatory functions prior to GC formation. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Follicular regulatory T (Tfr) cells are a regulatory T cell subset that controls antibody production by inhibiting T follicular helper (Tfh)–mediated help to B cells. Tfh and Tfr cells possess opposing functions suggesting unique programming. Here we elucidated the transcriptional program controlling Tfr suppressive function. We found that Tfr cells have a program for suppressive function fine-tuned by tissue microenvironment. The transcription factor FoxP3 and chromatin-modifying enzyme EZH2 are essential for this transcriptional program but regulate the program in distinct ways. FoxP3 modifies the Tfh program to induce a Tfr-like functional state, demonstrating that Tfr cells coopt the Tfh program for suppression. Importantly, we identified a Tfr cell population that loses the Tfr program to become “ex-Tfr” cells with altered functionality. These dysfunctional ex-Tfr cells may have roles in modulating pathogenic antibody responses. Taken together, our studies reveal mechanisms controlling the Tfr transcriptional program and how failure of these mechanisms leads to dysfunctional Tfr cells.

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