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.

Interleukin-17 (IL-17)-producing helper T (TH) cells, named as TH_IL-17, TH17, or inflammatory TH (THi), have been recently identified as a novel effector lineage. However, how cytokine signals mediate THi differentiation is unclear. We found that IL-6 functioned to up-regulate IL-23R and that IL-23 synergized with IL-6 in promoting THi generation. STAT3, activated by both IL-6 and IL-23, plays a critical role in THi development. A hyperactive form of STAT3 promoted THi development, whereas this differentiation process was greatly impaired in STAT3-deficient T cells. Moreover, STAT3 regulated the expression of retinoic acid receptor-related orphan receptor γ-T (RORγt), a THi-specific transcriptional regulator; STAT3 deficiency impaired RORγt expression and led to elevated expression of T-box expressed in T cells (T-bet) and Forkhead box P3 (Foxp3). Our data thus demonstrate a pathway whereby cytokines regulate THi differentiation through a selective STAT transcription factor that functions to regulate lineage-specific gene expression.