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1
* Department of Pathology and Center for Immunology, and
Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110
The role of type I IFN in Th1 development, STAT4 activation, and IFN-
production in murine T cells has remained unresolved despite extensive examination. Initial studies indicated that IFN-
induced Th1 development and IFN- production in human, but not murine, T cells, suggesting species-specific differences in signaling. Later studies suggested that IFN- also induced Th1 development in mice, similar to IL-12. More recent studies have questioned whether IFN- actually induces Th1 development even in the human system. In the present study, we compared the capacity of IL-12 and IFN- to induce Th1 differentiation, STAT4 phosphorylation, and IFN- production in murine T cells. First, we show that IFN-, in contrast to IL-12, cannot induce Th1 development. However, in differentiated Th1 cells, IFN- can induce transient, but not sustained, STAT4 phosphorylation and, in synergy with IL-18, can induce transient, but not sustained, IFN- production in Th1 cells, in contrast to the sustained actions of IL-12. Furthermore, loss of STAT1 increases IFN--induced STAT4 phosphorylation, but does not generate levels of STAT4 activation or IFN- 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--induced STAT4 activation is transient and unable to induce Th1 development, and indicate that IFN- may act similarly in human and murine T cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This research was supported by the Howard Hughes Medical Institute (to K.M.M.) and grants from the National Institutes of Health (P01 AI31238 and P50 HL54619; to K.M.M.).
2 Current address: Center for Immunology and Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
3 Address correspondence and reprint requests to Dr. Kenneth M. Murphy, Department of Pathology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address: murphy{at}pathbox.wustl.edu
4 Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; ICS, intracellular cytokine staining; IFNAR, IFN- receptor; KI, knock-in; m/h, mouse/human; MFI, median fluorescence intensity; pICS, intracellular phosphoprotein staining; pSTAT4, phosphorylated STAT4; SOCS, suppressors of cytokine signaling; WT, wild type.
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