IL-27 Regulates IL-12 Responsiveness of naïve CD4+T Cells through Stat1-Dependent and -Independent Mechanisms

IL-27, a novel heterodimeric cytokine produced by antigen-presenting cells, signals through the T cell cytokine receptor (TCCR)/WSX-1expressed on$na{\ddot \imath} ve\>CD4^+$T cells and natural killer cells. TCCR/WSX-1deficiency results in delayed T helper type 1 (TH1) development through an unresolved mechanism. We report here that IL-27 stimulation in developing murine T helper cells potently induces the expression of the major TH1-specific transcription factor T-bet and its downstream target IL-12R β 2, independently of IFNγ. In addition, IL-27 suppresses basal expression of GATA-3, the critical TH2-specific transcription factor that inhibits TH1development by down-regulating signal transducer and activator of transcription (Stat) 4. IL-27 signaling through TCCR/WSX-1induces phosphorylation of Stat1, Stat3, Stat4, and Stat5. Stat1 is required for suppression of GATA-3, but T-bet induction by IL-27 can also be mediated through a Stat1-independent pathway. Despite its TH1-like signaling profile, IL-27 is not sufficient to drive the differentiation of CD4+T cells into IFNγ-producing cells. Similarly, IL-27 induces T-bet expression in primary natural killer cells, but this does not result in an increase of IFNγ production or cytotoxic activity. Therefore, although IL-27 is unable to drive IFNγ production on its own, it plays an important role in the early steps of TH1commitment by contributing in a paracrine manner to the control of IL-12 responsiveness.