Significance This report brings a new perspective on the decades-old question of how MHC and HLA complexes can potently protect against a variety of autoimmune diseases, including type 1 diabetes. We demonstrated that protection by the MHC-II Eα:Eβ complex operated via modulation of the composition of the intestinal microbiota during a critical early window of ontogeny, associated with modification of the local immune system. These findings prompt a model of HLA/MHC-mediated protection from autoimmunity, and raise the question of whether disease-protective alleles in other human autoimmune diseases or models thereof might operate by a similar mechanism. They also argue that treating infants and pregnant mothers with antibiotics should be minimized.