Regulation of IL-12/IL-18-induced IFN-gamma production under Th2 condition.

摘要

Interferon (IFN)-γ is a significant component of innate and adaptive immune response against intracellular pathogens. CD4+ and CD8 + T cells produce IFN-γ via two pharmacologically distinct pathways: the TCR pathway and the IL-12/IL-18 pathway. The IL-12/IL-18 pathway has three significant characteristics: it elicits IFN-γ from T cells in an antigen-independent manner, it is operative in various cells of innate and adaptive immune response, and finally it is a biologically significant source of IFN-γ, as evidenced by marked reduction of IFN-γ production in IL-18−/− mice.; In CD4+ T cells, the IL-12/IL-18 pathway is regulated by cytokines. One mechanism of this regulation is cytokine-inducible expression of IL-12Rβ2, the signaling subunit of IL-12 receptor. IL-12 and IFN-γ, signaling via Stat4 and Stat1 respectively, induce IL-12Rβ2 expression, while IL-4, signaling through Stat6, down-regulates IL-12Rβ2 expression. The molecular details distal to Stats remain unknown. We evaluated the role of T-bet, a recently identified Th1-specific transcription factor, in regulation of IL-12Rβ2 expression. We found that T-bet was induced by IFN-γ via Statland that its ectopic expression induced IL-12Rβ2 expression, even in absence of Stat1. In contrast to previous reports, we did not find T-bet expression to fully induce Thl development, nor repress Th2 development. Thus, T-bet is a Stat1-induced regulator of IL-12Rβ2 expression in CD4+ T cells.; The regulation of the IL-12/IL-18 pathway in CD8+ cells is not as well characterized. Under Th1 condition, both CD4+ and CD8+ cells can produce IFN-γ in response to IL-12/IL-18, i.e. become IL-12/IL-18 responsive. However, under Th2 condition, CD8 + cells remain IL-12/IL-18 responsive, while CD4+ cells lose responsiveness. By mixing cultures of Th2-primed CD4+ and CD8+ cells, we found that the difference in IL-12/IL-18 responsiveness was cell-intrinsic. At least one mechanism of this cell-intrinsic difference was maintenance of IL-12Rβ2 expression in Th2-primed CD8 +, but not CD4+, T cells. Th2-primed CD8+ cells then upregulated IL-18Rα and β expression in response to IL-12 and IL-18. Furthermore, we found that Th2-primed CD8+, but not CD4+, cells expressed T-bet during development and upon restimulation. Thus continued T-bet expression may provide a mechanism for maintenance of IL-12Rβ2 expression in Th2-primed CD8+ cells.