Graft-versus-host disease (GvHD) remains the most significant complication after allogeneic stem cell transplantation (allo-SCT). Previously, acute GvHD had been considered to be mediated predominantly by Th1 polarized T cells. Recently, investigators have identified a second pro-inflammatory lineage of T cells termed Th17 that is critically dependent on the transcription factor RORγt. Here, we have evaluated the role of Th17 cells in murine acute GvHD by infusing donor T cells lacking RORC and as a consequence the isoform RORγt. Recipients given donor CD4+ and CD8+ T cells lacking RORC had significantly attenuated acute GvHD and markedly decreased tissue pathology in the colon, liver, and lung. Using a clinically relevant haploidentical murine transplantation model, we showed that RORC−/− CD4+ T cells alone diminished the severity and lethality of aGvHD. This was not found when CD4+ T cells from RORC−/− mice were given to completely mismatched BALB/c mice, and correlated with absolute differences in the generation of TNF in the colon post transplant. Thus, CD4+ T cell expression of RORC is important in the pathogenesis of acute GVHD
