The Journal of Experimental Medicine
Cytokines in immune regulation
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Published 6 July 2004. doi:10.1084/jem.20031819
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 1, 79-87
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Loss of T-bet, But Not STAT1, Prevents the Development of Experimental Autoimmune Encephalomyelitis

Estelle Bettelli1, Brandon Sullivan2, Susanne J. Szabo2, Raymond A. Sobel3,4, Laurie H. Glimcher2, and Vijay K. Kuchroo1

1 Center for Neurologic Diseases, Brigham and Women's Hospital, and 2 Department of Immunology and Infectious Diseases, Harvard School of Public Health, and Department of Medicine, Harvard Medical School, Boston, MA 02115
3 Laboratory Service, Veterans Affairs Health Care System, Palo Alto, CA 94304
4 Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305

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: vkuchroo{at}rics.bwh.harvard.edu

The transcription factors signal transducer and activator of transcription (STAT)1 and T-bet control the differentiation of interferon (IFN)-{gamma}–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-{gamma}–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-{gamma} gene transcription, our results demonstrate marked differences in their function in regulating pathogenic Th1 cell responses.

Key Words: MOG • 2D2 TCR transgenic mice • Th1 cell • IL-10 • chemokines

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.


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