IFN-γ–driven MHC class II on gut epithelium induces cytolytic T H 1 cell differentiation and stem cell loss in graft-versus-host disease

The molecular cues by which CD4 T cells are invoked to mediate lethal gut graft-versus-host disease (GVHD) at the epithelial interface after allogeneic hematopoietic stem cell transplantation are unclear. Here, we demonstrate that MHC class II (MHCII) but not MHC class I expression by intestinal epithelial cells (IECs) within the first 3 days of transplantation promotes lethal GVHD in mice. This was dependent on direct IFN-γ–dependent induction of MHCII on IECs, which expanded perforin/granzyme B–expressing cytolytic donor T H 1 cell while restraining T H 17 cell differentiation locally within the ileum. In contrast, intestinal stem cells (ISCs) were preferentially and progressively depleted by cytolytic T H 1 cells as a result of IFN-γ–induced MHCII expression. Together, IEC-intrinsic IFN-γ signaling is critical for the MHCII-dependent early local generation of cytolytic T H 1 cells that thereafter mediate MHCII-dependent ISC deletion. These data demonstrate a critical IFN-γ–MHCII feed-forward axis in the initiation of cytolytic T H 1 cell–dependent gut disease.