IL-27 regulates IL-12 responsiveness of naive 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-1) expressed on naive CD4(+) T cells and natural killer cells. TCCR/WSX-1 deficiency results in delayed T helper type 1 (T(H)1) 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 T(H)1-specific transcription factor T-bet and its downstream target IL-12R beta2, independently of IFN-gamma. In addition, IL-27 suppresses basal expression of GATA-3, the critical T(H)2-specific transcription factor that inhibits T(H)1 development by down-regulating signal transducer and activator of transcription (Stat) 4. IL-27 signaling through TCCR/WSX-1 induces 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 T(H)1-like signaling profile, IL-27 is not sufficient to drive the differentiation of CD4(+) T cells into IFNgamma-producing cells. Similarly, IL-27 induces T-bet expression in primary natural killer cells, but this does not result in an increase of IFNgamma production or cytotoxic activity. Therefore, although IL-27 is unable to drive IFNgamma production on its own, it plays an important role in the early steps of T(H)1 commitment by contributing in a paracrine manner to the control of IL-12 responsiveness.