The Role of Stat4 in Species-Specific Regulation of Th Cell Development by Type I IFNs

Abstract

Type I IFNs (IFN-α/β), in addition to IL-12, have been shown to play an important role in the differentiation of human, but not mouse, Th cells. We show here that IFN-α/β act directly on human T cells to drive Th1 development, bypassing the need for IL-12-induced signaling, whereas IFN-α cannot substitute IL-12 for mouse Th1 development. The molecular basis for this species specificity is that IFN-α/β activate Stat4 in differentiating human, but not mouse, Th cells. Unlike IL-12, which acts only on Th1 cells, IFN-α/β can activate Stat4 not only in human Th1, but also in Th2 cells. However, restimulation of human Th2 lines and clones in the presence of IFN-α does not induce the production of IFN-γ. These results suggest that activation of Stat4, which is necessary for the differentiation of naive T cells into polarized Th1 cells, is not sufficient to induce phenotype reversal of human Th2 cells.