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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5 July 2004
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July 06 2004
Loss of T-bet, But Not STAT1, Prevents the Development of Experimental Autoimmune Encephalomyelitis
Estelle Bettelli,
Estelle Bettelli
1Center for Neurologic Diseases, Brigham and Women's Hospital,
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Brandon Sullivan,
Brandon Sullivan
2Department of Immunology and Infectious Diseases, Harvard School of Public Health, and Department of Medicine, Harvard Medical School, Boston, MA 02115
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Susanne J. Szabo,
Susanne J. Szabo
2Department of Immunology and Infectious Diseases, Harvard School of Public Health, and Department of Medicine, Harvard Medical School, Boston, MA 02115
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Raymond A. Sobel,
Raymond A. Sobel
3Laboratory Service, Veterans Affairs Health Care System, Palo Alto, CA 94304
4Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305
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Laurie H. Glimcher,
Laurie H. Glimcher
2Department of Immunology and Infectious Diseases, Harvard School of Public Health, and Department of Medicine, Harvard Medical School, Boston, MA 02115
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Vijay K. Kuchroo
Vijay K. Kuchroo
1Center for Neurologic Diseases, Brigham and Women's Hospital,
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Estelle Bettelli
1Center for Neurologic Diseases, Brigham and Women's Hospital,
Brandon Sullivan
2Department of Immunology and Infectious Diseases, Harvard School of Public Health, and Department of Medicine, Harvard Medical School, Boston, MA 02115
Susanne J. Szabo
2Department of Immunology and Infectious Diseases, Harvard School of Public Health, and Department of Medicine, Harvard Medical School, Boston, MA 02115
Raymond A. Sobel
3Laboratory Service, Veterans Affairs Health Care System, Palo Alto, CA 94304
4Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305
Laurie H. Glimcher
2Department of Immunology and Infectious Diseases, Harvard School of Public Health, and Department of Medicine, Harvard Medical School, Boston, MA 02115
Vijay K. Kuchroo
1Center for Neurologic Diseases, Brigham and Women's Hospital,
Address correspondence to Vijay K. Kuchroo, Center for Neurologic Diseases, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115. Phone: (617) 252-5350; Fax: (617) 525-5333; email: [email protected]
Abbreviations used in this paper: CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; MIP, macrophage inflammatory protein; MOG, myelin oligodendrocyte glycoprotein; STAT, signal transducer and activator of transcription.
Received:
October 17 2003
Accepted:
May 25 2004
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2004
J Exp Med (2004) 200 (1): 79–87.
Article history
Received:
October 17 2003
Accepted:
May 25 2004
Citation
Estelle Bettelli, Brandon Sullivan, Susanne J. Szabo, Raymond A. Sobel, Laurie H. Glimcher, Vijay K. Kuchroo; Loss of T-bet, But Not STAT1, Prevents the Development of Experimental Autoimmune Encephalomyelitis . J Exp Med 5 July 2004; 200 (1): 79–87. doi: https://doi.org/10.1084/jem.20031819
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