Role of IFN-γ and IL-12 in Silencing the IL-4-Producing Potential in Th1 Cells (87.29)

Abstract To develop into committed Th1 cells, naive CD4+ T cells not only need to acquire the capacity to produce IFN-γ, but also need to silence the IL-4-producing potential. The role of IFN-γ is thought to primarily upregulate the IL-12β2 chain expression and thus enhances the IL-12 responsiveness. The direct effect of IFN-γ in Th1 cell development remains less clear. Furthermore, it is not clear whether both the IFN-γ and the IL-12 pathway are critical in silencing the IL-4-producing potential in Th1 cells. In this study, we investigated the role of the IFN-γ and the IL-12 pathways in silencing the IL-4-producing potential in Th1 cells. We found that IFN-γ was essential in silencing the IL-4-producing potential in Th1 cells, while IL-12 only partially suppressed the IL-4-producing potential. IL-12 completely depended on STAT4, while IFN-γ completely depended on STAT1 to suppress the IL-4-producing potential. Interestingly, T-bet is only partially required for IFN-γ to silence the IL-4-producing potential, whereas it is absolutely required for IL-12 to suppress the IL-4-producing potential. Our study clarifies the role of IFNγ-STAT1-T-bet and IL-12-STAT4-T-bet pathway in silencing the IL-4-protential during Th1 cell development, indicating that an additional factor, whose induction is STAT1 signaling, may be critical in Th1 cell commitment. This work is funded by an NIH grant (RO1 AI48568).