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

Abstract The factors initiating pathology in the gastrointestinal (GI) tract are largely unknown. Graft-versus-host disease (GVHD) of the gastrointestinal (GI) tract is the principal determinant of lethality following allogeneic bone marrow transplantation (BMT). MHC class II-dependent GVHD is initiated by recipient alloantigens being presented to donor T cells that in turn undergo Th1 and Th17 differentiation to mediate pathology in the GI tract. Critically, the mechanisms that initiate disease, especially the relevant antigen presenting cells, remain unclear. 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). The latter controls MHC class II expression and antigen presentation by intestinal epithelial cells (IEC) specifically within the ileum. When these tightly regulated responses between microbiome and lamina propria lymphocytes are perturbed by inflammatory signals driven by pre-transplant conditioning, dramatic increases in antigen presentation by IEC occur in the ileum and lethal GVHD ensues. Conditional and Villin-specific deletion of MHC class II in IEC, or inhibition of IL-12 pre-transplant, completely prevent the initiation of lethal GVHD, identifying a readily translatable therapeutic strategy.