T-bet is critical for the development of acute graft-versus-host disease through controlling T cell differentiation and function

J Fu, D Wang, Y Yu, J Heinrichs, Y Wu… - The Journal of …, 2015 - journals.aai.org
J Fu, D Wang, Y Yu, J Heinrichs, Y Wu, S Schutt, K Kaosaard, C Liu, K Haarberg, D Bastian…
The Journal of Immunology, 2015journals.aai.org
T-bet is a master regulator for IFN-γ production and Th1 differentiation. We evaluated the
roles of T-bet and IFN-γ 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-
γ−/− counterparts in both MHC-mismatched and MHC-matched but minor histocompatibility
Ag–mismatched models driven by CD4 T cells. T-bet−/−, but not IFN-γ−/−, CD4 T cells had a
markedly reduced ability to cause tissue damage in liver and gut. This distinct outcome is …
Abstract
T-bet is a master regulator for IFN-γ production and Th1 differentiation. We evaluated the roles of T-bet and IFN-γ 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-γ−/− counterparts in both MHC-mismatched and MHC-matched but minor histocompatibility Ag–mismatched models driven by CD4 T cells. T-bet−/−, but not IFN-γ−/−, 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-γ. 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-γ, such as CXCR3 and programmed death-1, or systematic IFN-γ, such as NKG2D, IA b, and granzyme B. Although both T-bet−/− and IFN-γ−/− CD4 T cells are prone to differentiate into Th17 cells, polarized Th17 cells deficient for T-bet but not for IFN-γ 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-γ may be a promising strategy to control GVHD in the clinic.
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