Tbet is a critical modulator of FoxP3 expression in autoimmune graft-versus-host disease

CD4(+) T-helper subsets drive autoimmune chronic graft-versus-host disease, a major complication after allogeneic bone marrow transplantation. However, it remains unclear how specific T-helper subsets contribute to chronic graft-versus-host disease. T-helper type 1 cells are one of the major disease-mediating T-cell subsets and require interferon-γ signaling and Tbet expression for their function. Regulatory T cells on the other hand can inhibit T-helper type 1 cell-mediated responses. Using an established murine model that isolates the autoimmune component of graft-versus-host disease, we hypothesized that T-helper type 1 cells would restrict FoxP3-driven regulatory T cells. Upon transfer into immune-deficient syngeneic hosts, alloreactive Tbx21(−/−)CD4(+) T cells led to marked increases in FoxP3(+) cells and reduced clinical evidence of autoimmunity. To evaluate whether peripheral induction contributed to regulatory T-cell predominance, we adoptively transferred Tbx21(−/−) T cells that consisted of fate mapping for FoxP3: recipients of flow-purified effector cells that were Foxp3(−) and Tbx21(−/−) had enhanced T-regulatory-cell predominance during autoimmune graft-versus-host disease. These data directly demonstrated that peripheral T-regulatory-cell induction was inhibited by Tbet. Finally, Tbx21(−/−) T-regulatory cells cross-regulated autoimmune wild-type T-effector-cell cytokine production in vivo. The Tbet pathway therefore directly impairs T-regulatory-cell reconstitution and is consequently a feasible target in efforts to prevent autoimmune graft-versus-host disease.