Follicular regulatory T (Tfr) cells with dual Foxp3 and Bcl6 expression 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 T(reg) cells expressing CXCR5 and Bcl6, and localized in the germinal centers in mouse as well as human. The expression of CXCR5 on T(reg) cells depends on Bcl6. These CXCR5(+)Bcl6(+) T(reg) cells are absent in thymus but can be de novo generated from CXCR5(-)Foxp3(+) natural T(reg) precursors. Lack of CXCR5(+) T(reg) cells leads to greater germinal center reactions. These results unveil a Bcl6-CXCR5 axis in T(reg) cells that undermines the development of follicular regulatory T (Tfr) cells that function to inhibit the germinal center reaction.