Type 17 immune cells, typified by the expression of IL-17 family cytokines IL-17A and IL-17F, are involved in numerous organ specific autoimmune syndromes. This class of immune cells has been implicated in the pathogenesis of type 1 diabetes (T1D) however the relevant mechanisms have not been established. To study the role of IL-17 receptors in T1D we generated a novel line of IL-17 receptor C (IL-17RC) deficient Non-Obese Diabetic (NOD) mice, which were insensitive to both IL-17A and IL-17F. Diabetes incidence studies demonstrated that IL-17RC deficient NOD mice were strongly protected from the development of T1D. This phenotype was dependent upon specific breeding and housing conditions, suggesting that environmental factors regulate diabetes protection in this model.
Previous studies demonstrate that IL-17RC plays critical roles in intestinal immune homeostasis, while there is strong evidence that gut microbiota regulate the development of T1D. To determine whether IL-17RC knockout NOD mice had an altered gut microbiome we performed 16S rRNA sequencing on faecal samples, which revealed distinct changes in the microbiome of IL-17RC knockout NOD mice. Phenotypic analysis of immune markers identified a significant reduction in islet antigen reactive IGRP tetramer+ CD8+ T cells in IL-17RC knockout NOD mice, indicative of impaired autoimmune responses. In addition, IL-17RC knockout NOD mice exhibited increased frequencies of IL-10 producing CD4+ T cells in spleen and gut draining lymph nodes. Together these data indicate that diabetes protection in IL-17RC knockout NOD mice is correlated with changes in the gut microbiome and expansion of regulatory T cell lineages.