Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions

Foxp3(+) regulatory T (T-reg) cells suppress different types of immune responses to help maintain homeostasis in the body. How T-reg cells regulate humoral immunity, including germinal center reactions, is unclear. Here we identify a subset of Treg cells expressing CXCR5 and Bcl-6 that localize to the germinal centers in mice and humans. The expression of CXCR5 on T-reg cells depends on Bcl-6. These CXCR5(+) Bcl-6(+) T-reg cells are absent in the thymus but can be generated de novo from CXCR5-Foxp3(+) natural T-reg precursors. A lack of CXCR5+ T-reg cells leads to greater germinal center reactions including germinal center B cells, affinity maturation of antibodies and the differentiation of plasma cells. These results unveil a Bcl-6-CXCR5 axis in T-reg cells that drives the development of follicular regulatory T (T-FR) cells that function to inhibit the germinal center reactions.