期刊
JOURNAL OF IMMUNOLOGY
卷 194, 期 1, 页码 388-397出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1401618
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资金
- National Institutes of Health [R01 CA143812, R01 CA169116]
T-bet is a master regulator for IFN-gamma production and Th1 differentiation. We evaluated the roles of T-bet and IFN-gamma in T cell responses in acute graft-versus-host disease (GVHD) and found that T-bet(-/-) T cells induced significantly less GVHD compared with wild-type or IFN-gamma(-/-) counterparts in both MHC-mismatched and MHC-matched but minor histocompatibility Ag-mismatched models driven by CD4 T cells. T-bet(-/-), but not IFN-g(-/-), CD4 T cells had a markedly reduced ability to cause tissue damage in liver and gut. This distinct outcome is reflected by the differential gene expression on donor CD4 T cells deficient for T-bet or IFN-gamma. At mRNA and protein levels, we defined several T-bet-dependent molecules that may account for the impaired ability of T-bet(-/-) T cells to migrate into target organs and to produce Th1-related cytokines. Moreover, these molecules were independent of either endogenous IFN-gamma, such as CXCR3 and programmed death-1, or systematic IFN-gamma, such as NKG2D, I-A(b), and granzyme B. Although both T-bet(-/-) and IFN-g(-/-) CD4 T cells are prone to differentiate into Th17 cells, polarized Th17 cells deficient for T-bet but not for IFN-gamma had a significantly reduced ability to cause GVHD. Finally, T-bet(-/-) T cells had a compromised graft-versus-leukemia effect, which could be essentially reversed by neutralization of IL-17 in the recipients. We conclude that T-bet is required for Th1 differentiation and migration, as well as for optimal function of Th17 cells. Thus, targeting T-bet or regulating its downstream effectors independent of IFN-gamma may be a promising strategy to control GVHD in the clinic.
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