The heterodimeric cytokine interleukin 27 (IL-27) signals through the IL-27Rα subunit of its receptor, combined with gp130, a common receptor chain used by several cytokines, including IL-6. Notably, the IL-27 subunits p28 (IL-27p28) and EBI3 are not always expressed together, which suggests that they may have unique functions. Here we show that IL-27p28, independently of EBI3, antagonized cytokine signaling through gp130 and IL-6-mediated production of IL-17 and IL-10. Similarly, the ability to generate antibody responses was dependent on the activity of gp130-signaling cytokines. Mice transgenic for expression of IL-27p28 showed a substantial defect in the formation of germinal centers and antibody production. Thus, IL-27p28, as a natural antagonist of gp130-mediated signaling, may be useful as a therapeutic for managing inflammation mediated by cytokines that signal through gp130.

Helper T cells control host defense against pathogens. The receptors for interleukin 12 (IL-12), IL-4 and IL-6 are required for differentiation into the T(H)1, T(H)2 and T(H)17 subsets of helper T cells, respectively. IL-2 signaling via the transcription factor STAT5 controls T(H)2 differentiation by regulating both the T(H)2 cytokine gene cluster and expression of Il4ra, the gene encoding the IL-4 receptor α-chain. Here we show that IL-2 regulated T(H)1 differentiation, inducing STAT5-dependent expression of the IL-12 receptor β2-chain (IL-12Rβ2) and the transcription factor T-bet, with impaired human T(H)1 differentiation when IL-2 was blocked. T(H)1 differentiation was also impaired in mouse Il2(-/-) T cells but was restored by IL-12Rβ2 expression. Consistent with the inhibition of T(H)17 differentiation by IL-2, treatment with IL-2 resulted in lower expression of the genes encoding the IL-6 receptor α-chain (Il6ra) and the IL-6 signal transducer gp130 (encoded by Il6st), and retroviral transduction of Il6st augmented T(H)17 differentiation even when IL-2 was present. Thus, IL-2 influences helper T cell differentiation by modulating the expression of cytokine receptors to help specify and maintain differentiated states.

Follicular helper T cells (T(FH) cells) are specialized effector CD4(+) T cells that help B cells develop germinal centers (GCs) and memory. However, the transcription factors that regulate the differentiation of T(FH) cells remain incompletely understood. Here we report that selective loss of Lef1 or Tcf7 (which encode the transcription factor LEF-1 or TCF-1, respectively) resulted in T(FH) cell defects, while deletion of both Lef1 and Tcf7 severely impaired the differentiation of T(FH) cells and the formation of GCs. Forced expression of LEF-1 enhanced T(FH) differentiation. LEF-1 and TCF-1 coordinated such differentiation by two general mechanisms. First, they established the responsiveness of naive CD4(+) T cells to T(FH) cell signals. Second, they promoted early T(FH) differentiation via the multipronged approach of sustaining expression of the cytokine receptors IL-6Rα and gp130, enhancing expression of the costimulatory receptor ICOS and promoting expression of the transcriptional repressor Bcl6.