TY - JOUR
T1 - T-bet Is critical for the development of acute graft-versus-host disease through controlling T cell differentiation and function
AU - Fu, Jianing
AU - Wang, Dapeng
AU - Yu, Yu
AU - Heinrichs, Jessica
AU - Wu, Yongxia
AU - Schutt, Steven
AU - Kaosaard, Kane
AU - Liu, Chen
AU - Haarberg, Kelley
AU - Bastian, David
AU - McDonald, Daniel G.
AU - Anasetti, Claudio
AU - Yu, Xue Zhong
N1 - Publisher Copyright:
Copyright © 2014 by The American Association of Immunologists, Inc.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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-bet2/2 T cells induced significantly less GVHD compared with wild-type or IFN-γ2/2 counterparts in both MHC-mismatched and MHC-matched but minor histocompatibility Ag-mismatched models driven by CD4 T cells. T-bet2/2, but not IFN-γ2/2, 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-bet2/2 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, I-Ab, and granzyme B. Although both T-bet2/2 and IFN-γ2/2 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-bet2/2 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.
AB - 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-bet2/2 T cells induced significantly less GVHD compared with wild-type or IFN-γ2/2 counterparts in both MHC-mismatched and MHC-matched but minor histocompatibility Ag-mismatched models driven by CD4 T cells. T-bet2/2, but not IFN-γ2/2, 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-bet2/2 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, I-Ab, and granzyme B. Although both T-bet2/2 and IFN-γ2/2 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-bet2/2 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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U2 - 10.4049/jimmunol.1401618
DO - 10.4049/jimmunol.1401618
M3 - Article
C2 - 25404360
AN - SCOPUS:84919663260
SN - 0022-1767
VL - 194
SP - 388
EP - 397
JO - Journal of Immunology
JF - Journal of Immunology
IS - 1
ER -