Immune responses to the microbiome tune MHC-II antigen presentation by the intestinal epithelium to control gut pathology

The factors initiating pathology in the gastrointestinal (GI) tract are largely unknown. GI tract pathology is the principal determinant of lethality following allogeneic bone marrow transplantation (BMT). MHC-class-II-dependent graft-versus-host-disease (GVHD) is initiated byrecipient alloantigens being presented to donor T-cells that in turn mediate damage in the GI tract. Critically, the mechanisms that initiate disease, including the relevant antigen presenting cells,remain unknown. Here, we identify the response of IL-12-secreting macrophages to the microbiome as the key driver of IFNγ secretion by mucosal type-1 innate-lymphoid-cells (ILC1). These responses control MHC-class-II expression by intestinal epithelial cells (IEC) within the ileum. When these tightly regulated responses between microbiome and lamina propria lymphocytes are perturbed by inflammatory signals driven by pre-transplant conditioning, lethal intestinal GVHD ensues. Villin-specific deletion of MHC-class-II in IEC, or inhibition of IL-12 pre-transplant, prevent the initiation of lethal GVHD in the GI tract, identifying a readily translatable therapeutic strategy.