Follicular helper T (TFH) 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 TFH cells. We found that a proportion of follicular T cells, with phenotypic characteristics of TFH 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 TFH and regulatory T cells for the control of humoral immune responses.

The significance of cytokine production by CD4+ regulatory T (T reg) cells after antigen exposure in vivo and its impact on their regulatory activity remains unclear. Pretreatment with donor alloantigen under the cover of anti-CD4 therapy generates alloantigen reactive T reg cells that can prevent rejection of donor-specific skin grafts that are mediated by naive CD45RBhighCD4+ T cells. To examine the kinetics and importance of cytokine gene transcription by such alloantigen-reactive T reg cells, pretreated mice were rechallenged with donor alloantigen in vivo. CD25+CD4+ T cells, but not CD25−CD4+ T cells, showed a fivefold increase in IFN-γ mRNA expression within 24 h of reencountering alloantigen in vivo. This expression kinetic was highly antigen-specific and was of functional significance. Neutralizing IFN-γ at the time of cotransfer of alloantigen reactive T reg cells, together with CD45RBhighCD4+ effector T cells into Rag −/− skin graft recipients, resulted in skin graft necrosis in all recipients; the generation and function of alloantigen-reactive T reg cells was impaired dramatically in IFN-γ–deficient mice. These data support a unique role for IFN-γ in the functional activity of alloantigen-reactive T reg cells during the development of operational tolerance to donor alloantigens in vivo.

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