Follicular helper T (T_FH) cells participate in humoral responses providing selection signals to germinal center B cells. Recently, expression of CXCR5, PD-1, and the transcription factor Bcl-6 has allowed the identification of T_FH cells. We found that a proportion of follicular T cells, with phenotypic characteristics of T_FH cells and expressing Foxp3, are recruited during the course of a germinal center (GC) reaction. These Foxp3⁺ cells derive from natural regulatory T cells. To establish the in vivo physiologic importance of Foxp3⁺ follicular T cells, we used CXCR5-deficient Foxp3⁺ cells, which do not have access to the follicular region. Adoptive cell transfers of CXCR5-deficient Foxp3⁺ cells have shown that Foxp3⁺ follicular T cells are important regulators of the GC reaction following immunization with a thymus-dependent Ag. Our in vivo data show that Foxp3⁺ follicular T cells can limit the magnitude of the GC reaction and also the amount of secreted Ag-specific IgM, IgG1, IgG2b, and IgA. Therefore, Foxp3⁺ follicular regulatory T cells appear to combine characteristics of T_FH and regulatory T cells for the control of humoral immune responses.

Immunization leads to the formation of germinal centres (GCs) that contain both T follicular helper (Tfh) and T follicular regulatory (Tfr) cells. Whether T-cell receptor (TCR) specificity defines the differential functions of Tfh and Tfr cells is unclear. Here we show that antigen-specific T cells after immunization are preferentially recruited to the GC to become Tfh cells, but not Tfr cells. Tfh cells, but not Tfr cells, also proliferate efficiently on restimulation with the same immunizing antigenin vitro.Ex vivoTCR repertoire analysis shows that immunization induces oligoclonal expansion of Tfh cells. By contrast, the Tfr pool has a TCR repertoire that more closely resembles that of regulatory T (Treg) cells. Our data thus indicate that the GC Tfh and Tfr pools are generated from distinct TCR repertoires, with Tfh cells expressing antigen-responsive TCRs to promote antibody responses, and Tfr cells expressing potentially autoreactive TCRs to suppress autoimmunity.