Loss of T-bet, But Not STAT1, Prevents the Development of Experimental Autoimmune Encephalomyelitis

Journal of Experimental Medicine - Tập 200 Số 1 - Trang 79-87 - 2004
Estelle Bettelli1, Brandon M. Sullivan2, Susanne J. Szabo2, Raymond A. Sobel3,4, Laurie H. Glimcher2, Vijay K. Kuchroo5
1Center for Neurologic Diseases, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
22Department of Immunology and Infectious Diseases, Harvard School of Public Health, and Department of Medicine, Harvard Medical School, Boston, MA 02115
33Laboratory Service, Veterans Affairs Health Care System, Palo Alto, CA 94304
44Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305
51Center for Neurologic Diseases, Brigham and Women's Hospital,

Tóm tắt

The transcription factors signal transducer and activator of transcription (STAT)1 and T-bet control the differentiation of interferon (IFN)-γ–producing T helper type (Th)1 cells. Here we compare the role of T-bet and STAT1 in the initiation and regulation of experimental autoimmune encephalomyelitis (EAE), a disease initiated by Th1 cells. T-bet–deficient mice immunized with myelin oligodendrocyte glycoprotein (MOG) were resistant to the development of EAE. This protection was also observed when T-bet−/− mice were crossed to the MOG-specific 2D2 T cell receptor transgenic strain. In contrast, although T-bet is downstream of STAT1, STAT1−/− mice were highly susceptible to EAE and developed more severe and accelerated disease with atypical neuropathologic features. The function of T-bet was dominant as mice deficient in both T-bet and STAT1 were also protected from EAE. CD4+ CD25+ regulatory T cells from these two mice strains were fully competent and do not explain the difference in disease susceptibility. However, enhanced EAE in STAT1−/− mice was associated with continued generation of IFN-γ–producing Th1 cells and up-regulation of selective chemokines responsible for the increased recruitment of macrophages and neutrophils in the central nervous system. Although the two transcription factors, STAT1 and T-bet, both induce IFN-γ gene transcription, our results demonstrate marked differences in their function in regulating pathogenic Th1 cell responses.

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Journal of Experimental Medicine

Tập 200 Số 1

79-87

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