A protective MHC class II molecule prevents autoimmune diabetes by selecting for specific intestinal microbes early in ontogeny

Abstract Type 1 diabetes (T1D) affects millions of people worldwide. The incidence has risen significantly over the past few decades. Both genetic and environmental factors contribute to T1D. Certain HLA haplotypes such as DRB1*1501-DQB1*0602 dominantly protect against T1D yet the mechanism of this remarkably protection remains unknown. We recently demonstrated that the protective major histocompatibility complex (MHC) E molecule prevents autoimmune diabetes in NOD mice by shaping the intestinal microbiome early in ontogeny. This finding presents a novel paradigm in which genetic protection from immune system dysregulation is mediated via commensal microbiota. An important gap in knowledge is which intestinal microbes prevent autoimmunity by modulating the immune system. We hypothesize that those microbes that differentially stimulate humoral immune responses in the previously reported MHCII E-expressing NOD (Eα16/NOD) mice may also modulate the immune system to prevent autoimmunity. We address this question by leveraging the exquisite sensitivity and specificity of the humoral immune system to identify a subset of microbes via flow cytometry that stimulate mucosal and/or systemic immune responses to prevent autoimmunity.