Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis

E Bettelli, B Sullivan, SJ Szabo, RA Sobel… - The Journal of …, 2004 - rupress.org
E Bettelli, B Sullivan, SJ Szabo, RA Sobel, LH Glimcher, VK Kuchroo
The Journal of experimental medicine, 2004rupress.org
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 …
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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