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

E. Bettelli,B. Sullivan,S. Szabo,R. Sobel,L. Glimcher,V. Kuchroo

Published 2004 in Journal of Experimental Medicine

ABSTRACT

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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