| Popis: |
The gut microbiota is essential for the normal function of the gut immune system and microbiota alterations are associated with autoimmune disorders. However how the gut microbiota influences the immune system in distant organs to prevent autoimmunity remains poorly defined. Here we reveal that the gut microbiota stimulates innate lymphoid cells (ILCs) in the pancreas leading to the expression of the mouse β-defensin 14 (mBD14) that prevents autoimmune diabetes in the non-obese diabetic (NOD) mouse model. Pancreatic endocrine cells constitutively express mBD14 in non-autoimmune mice but not in NOD mice. MBD14 stimulates, via TLR2, IL-4-secreting B cells that induce regulatory macrophages, which in turn induce regulatory T cells. The gut microbiota-derived molecules, AHR ligands and butyrate, promote IL-22 secretion by pancreatic type 3 ILCs that, in turn induces pancreatic expression of mBD14. Dysbiotic microbiota and low-affinity AHR allele explain the defective pancreatic expression of mBD14 in NOD mice. Our findings reveal a novel interplay between the gut microbiota and ILCs that contributes in maintaining pancreatic immune tolerance. |
