IL-27 regulates IL-12 responsiveness of naive CD4~+ T cells through Stat1-dependent and -independent mechanisms

摘要

IL-27, a novel heterodimeric cytokine produced by antigen-presenting cells, signals through the T cell cytokine receptor (TCCR)~(/WSX-1) expressed on naieve CD4~+ T cells and natural killer cells. TCCR~(/WSX-1) deficiency results in delayed T helper type 1 (T_H1) 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_H1-specific transcription factor T-bet and its downstream target IL-12R β2, independently of IFNγ. In addition, IL-27 suppresses basal expression of GATA-3, the critical T_H2-specific transcription factor that inhibits T_H1 development by down-regulating signal transducer and activator of transcription (Stat) 4. IL-27 signaling through TCCR~(/WSX-1) induces phos-phorylation 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_H1-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 T_H1 commitment by contributing in a paracrine manner to the control of IL-12 responsiveness.