ena-STUDY-QIMR BERGHOFER-31-07-2019-06:54:18:065-2085
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 IFN? 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.
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 IFN? 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.