| First Author | Fu J | Year | 2015 |
| Journal | J Immunol | Volume | 194 |
| Issue | 1 | Pages | 388-97 |
| PubMed ID | 25404360 | Mgi Jnum | J:230707 |
| Mgi Id | MGI:5763560 | Doi | 10.4049/jimmunol.1401618 |
| Citation | Fu J, et al. (2015) T-bet is critical for the development of acute graft-versus-host disease through controlling T cell differentiation and function. J Immunol 194(1):388-97 |
| abstractText | 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-gamma(-/-), 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-gamma(-/-) 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. |
