Distinct characteristics of murine STAT4 activation in response to IL-12 and IFN-α

The role of type I IFN in Th1 development, STAT4 activation, and IFN-γ production in murine T cells has remained unresolved despite extensive examination. Initial studies indicated that IFN-α induced Th1 development and IFN-γ production in human, but not murine, T cells, suggesting species-specific differences in signaling. Later studies suggested that IFN-α also induced Th1 development in mice, similar to IL-12. More recent studies have questioned whether IFN-α actually induces Th1 development even in the human system. In the present study, we compared the capacity of IL-12 and IFN-α to induce Th1 diferentiation, STAT4 phosphorylation, and IFN-γ production in marine T cells. First, we show that IFN-α, in contrast to IL-12, cannot induce Th1 development However, in differentiated Th1 cells, IFN-α can induce transient, but not sustained, STAT4 phosphorylation and, in synergy with IL-18, can induce transient, but not sustained, IFN-γ production in Th1 cells, in contrast to the sustained actions of IL-12. Furthermore, loss of STAT1 increases IFN-α-induced STAT4 phosphorylation, but does not generate levels of STAT4 activation or IFN-γ production achieved by IL-12 or convert transient STAT4 activation into a sustained response. Our findings agree with recent observations in human T cells that IFN-α-induced STAT4 activation is transient and unable to induce Th1 development, and indicate that IFN-α may act similarly in human and murine T cells.