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

Jianing Fu, Dapeng Wang, Yu Yu, Jessica Heinrichs, Yongxia Wu, Steven Schutt, Kane Kaosaard, Chen Liu, Kelley Haarberg, David Bastian, Daniel G. McDonald, Claudio Anasetti, Xue Zhong Yu

Research output: Contribution to journalArticle

17 Scopus citations

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-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.

Original languageEnglish (US)
Pages (from-to)388-397
Number of pages10
JournalJournal of Immunology
Volume194
Issue number1
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Fu, J., Wang, D., Yu, Y., Heinrichs, J., Wu, Y., Schutt, S., Kaosaard, K., Liu, C., Haarberg, K., Bastian, D., McDonald, D. G., Anasetti, C., & Yu, X. Z. (2015). T-bet Is critical for the development of acute graft-versus-host disease through controlling T cell differentiation and function. Journal of Immunology, 194(1), 388-397. https://doi.org/10.4049/jimmunol.1401618