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

Abstract

Germinal center B cell development is promoted by T follicular helper cells. Chen Dong and his colleagues show that Foxp3+ regulatory T cells expressing Bcl6 and CXCR5, two molecules highly expressed in T follicular helper cells, are present in humans and mice and arise from natural regulatory T cells. In vivo, these CXCR5+Bcl6+ regulatory T cells modulate germinal center responses. Foxp3+ regulatory T (Treg) cells suppress different types of immune responses to help maintain homeostasis in the body. How Treg 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 Treg cells depends on Bcl-6. These CXCR5+Bcl-6+ Treg cells are absent in the thymus but can be generated de novo from CXCR5−Foxp3+ natural Treg precursors. A lack of CXCR5+ Treg 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 Treg cells that drives the development of follicular regulatory T (TFR) cells that function to inhibit the germinal center reactions.