T-bet Is Critical for the Development of Acute Graft-versus-Host Disease through Controlling T Cell Differentiation and Function

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 to WT or IFN-γ−/− counterparts in both MHC-mismatched and MHC-matched but minor histocompatibility antigen (miHA)-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 PD-1, or systematic IFN-γ such as NKG2D, I-Ab, 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 compromised graft-versus-leukemia (GVL) 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.

T-bet Promotes Acute Graft-versus-Host Disease by Regulating Recipient Hematopoietic Cells in Mice

“…The less effect of T-bet −/− host cells on donor CD8 T cells may limit the effect on GVHD alleviation, but it likely contributes to the largely preserved GVL effect (Figure 9). The present study together with our previous published work (20) set a strong rationale to pharmacologically inhibit T-bet in vivo for the control of GVHD through targeting both donor T cells and recipient hematopoietic cells synchronously. Further studies are required to translate our findings towards clinical application.…”

“…Our group and others previously reported the fundamental role of the T-box transcription factor T-bet on T cells in GVHD, inflammatory diseases or autoimmune diseases (20-24). T-bet also regulates the activation and function of many APCs, such as DCs (25-27) and B cells (28, 29).…”

“…MHC- and miHA-mismatched (FVB→ B6; B6→BALB/c) or MHC-matched but miHA-mismatched (129S2/Sv→ B6; C3H.SW→ B6) BMT models were used as previously established (20, 33). Briefly, different strains of recipient mice were conditioned with a lethal dose of total body irradiation (TBI).…”

“…Spleens of DR5 −/− mice on B6 background and their wild type (WT) counterparts were kindly provided by Dr. Niklas Finnberg from Penn State Hershey Cancer Institute. H&E staining and a semi-quantitative scoring system were used to account for histologic changes consistent with GVHD in the target organs as previously described (20, 21, 35). …”

“…Tumor mortality and GVHD mortality were distinguished by BLI signal intensity and clinical manifestation of GVHD (20, 35). …”