T Follicular Helper Cell Differentiation: When B cells respond to an infection, they often require help from CD4 ⁺ T cells to mount a proper response. It is thought that a subset of CD4 ⁺ effector T cells, called T follicular helper cells (T _FH ), performs this function. Several subsets of effector CD4 ⁺ T cells arise, depending on the type of infection, which have distinct transcriptional programs driving their differentiation. Whether this is also the case for T _FH cells has not been clear (see the Perspective by Awasthi and Kuchroo ). Nurieva et al. (p. 1001 , published online 23 July) and Johnston et al. (p. 1006 ; published online 16 July) now demonstrate that the transcription factor Bcl6 is both necessary and sufficient for T _FH differentiation and subsequent B cell–mediated immunity, suggesting that it is a master regulator of this lineage. Johnston et al. also show that expression of Bcl6 and the transcription factor, Blimp-1, are reciprocally regulated in T _FH cells and that, when ectopically expressed, Blimp-1 inhibits T _FH development.

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.