Berenson Lisa S, Gavrieli Maya, Farrar J David, Murphy Theresa L, Murphy Kenneth M
Department of Pathology and Center for Immunology, Washington University of School of Medicine, St Louis, MO 63110, USA.
J Immunol. 2006 Oct 15;177(8):5195-203. doi: 10.4049/jimmunol.177.8.5195.
The role of type I IFN in Th1 development, STAT4 activation, and IFN-gamma production in murine T cells has remained unresolved despite extensive examination. Initial studies indicated that IFN-alpha induced Th1 development and IFN-gamma production in human, but not murine, T cells, suggesting species-specific differences in signaling. Later studies suggested that IFN-alpha also induced Th1 development in mice, similar to IL-12. More recent studies have questioned whether IFN-alpha actually induces Th1 development even in the human system. In the present study, we compared the capacity of IL-12 and IFN-alpha to induce Th1 differentiation, STAT4 phosphorylation, and IFN-gamma production in murine T cells. First, we show that IFN-alpha, in contrast to IL-12, cannot induce Th1 development. However, in differentiated Th1 cells, IFN-alpha can induce transient, but not sustained, STAT4 phosphorylation and, in synergy with IL-18, can induce transient, but not sustained, IFN-gamma production in Th1 cells, in contrast to the sustained actions of IL-12. Furthermore, loss of STAT1 increases IFN-alpha-induced STAT4 phosphorylation, but does not generate levels of STAT4 activation or IFN-gamma 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-alpha-induced STAT4 activation is transient and unable to induce Th1 development, and indicate that IFN-alpha may act similarly in human and murine T cells.
尽管进行了广泛研究，但I型干扰素在小鼠T细胞的Th1细胞发育、STAT4激活及干扰素-γ产生中的作用仍未明确。最初的研究表明，干扰素-α可诱导人而非小鼠T细胞的Th1细胞发育及干扰素-γ产生，提示信号传导存在种属特异性差异。后来的研究表明，干扰素-α也可诱导小鼠的Th1细胞发育，类似于白细胞介素-12。最近的研究对干扰素-α是否真的能在人类系统中诱导Th1细胞发育提出了质疑。在本研究中，我们比较了白细胞介素-12和干扰素-α在诱导小鼠T细胞Th1分化、STAT4磷酸化及干扰素-γ产生方面的能力。首先，我们发现，与白细胞介素-12不同，干扰素-α不能诱导Th1细胞发育。然而，在分化的Th1细胞中，干扰素-α可诱导短暂而非持续的STAT4磷酸化，并且与白细胞介素-18协同作用时，可诱导Th1细胞短暂而非持续的干扰素-γ产生，这与白细胞介素-12的持续作用相反。此外，STAT1缺失会增加干扰素-α诱导的STAT4磷酸化，但不会产生白细胞介素-12所达到的STAT4激活水平或干扰素-γ产生水平，也不会将短暂的STAT4激活转化为持续反应。我们的发现与最近在人类T细胞中的观察结果一致，即干扰素-α诱导的STAT4激活是短暂的，无法诱导Th1细胞发育，这表明干扰素-α在人类和小鼠T细胞中的作用可能相似。
