| Summary: | Host genetics plays an important role in shaping its intestinal microbiota. Additionally, it has been well established that the commensal microbiota is an important environmental factor that regulates autoimmunity. However, this depends on the type of autoimmune response modeled. Microbial influences range from protection, to no influence, to stimulation of disease pathology. Previous work had demonstrated that deletion of the innate immune adaptor myeloid differentiation primary response gene 88 (MyD88) in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D) results in microbiota-dependent protection from the disease. Thus MyD88-negative mice in germfree (GF), but not in specific pathogen-free conditions, develop disease. These results could be explained by expansion of protective bacteria ("specific lineage hypothesis") or by dominance of tolerizing signaling over proinflammatory signaling ("balanced signal hypothesis") in mutant mice. We found that colonization of GF NOD with a variety of intestinal bacteria had no effect on wild-type mice, but reduced T1D in MyD88-negative NOD. These results supported the balanced signal hypothesis, but the receptors and signaling pathways involved in prevention or promotion of the disease remained unknown. The protective signals triggered by the microbiota were revealed by testing NOD mice lacking MyD88 in combination with knockouts of critical components of innate immune sensing for rescue of T1D. Only MyD88- and TIR-domain containing adapter inducing IFN beta (TRIF) double deficient NOD mice developed the disease. Thus, TRIF signaling serves as one of the microbiota-induced tolerizing pathways, potentially by signaling through TLR4. TLR2 was shown to promote diabetic signaling, as the protection observed in TLR2-negative mice was eliminated when the mice were rederived into GF conditions. Our results support the balanced signal hypothesis, in which microbes provide signals that both promote and inhibit autoimmunity. The microbiota's influence on the host immune system is regulated by activation of different members of the TLR family of innate immune receptors.
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