IFN- Is Not Sufficient to Drive Th1 Development Due to Lack of Stable T-bet Expression

During inflammatory immune responses, the innate cytokine IL-12 promotes CD4 Th-1 development through the activation of the second messenger STAT4 and the subsequent expression of T-bet. In addition, type I IFN (IFN), secreted primarily during viral and intracellular bacterial infections, can promote STAT4 activation in human CD4 T cells. However, the role of IFNin regulating Th1 development is controversial, and previous studies have suggested a species-specific pathway leading to Th1 development in human but not mouse CD4 T cells. In this study, we found that although both IFNand IL-12 can promote STAT4 activation, IFNfailed to promote Th1 commitment in human CD4 T cells. The difference between these innate signaling pathways lies with the ability of IL-12 to promote sustained STAT4 tyrosine phosphorylation, which correlated with stable T-bet expression in committed Th1 cells. IFNdid not promote Th1 development in human CD4 T cells because of attenuated STAT4 phosphorylation, which was insufficient to induce stable expression of T-bet. Further, the defect in IFNdriven Th1 development was corrected by ectopic expression of T-bet within primary naive human CD4 T cells. These results indicate that IL-12 remains unique in its ability to drive Th1 development in human CD4 T cells and that IFNlacks this activity due to its inability to promote sustained T-bet expression. The Journal of Immunology, 2007, 179: 3792–3803.