The commensal microbiome heavily influences the host immune system and plays an integral role in immunity to infection and cancer. Conversely, changes in the microbiota have been linked with the development of autoimmune diseases, such as multiple sclerosis (MS). Here, we have used a murine model of MS, experimental autoimmune encephalomyelitis (EAE), to examine the role of the microbiome in priming pathogenic CD4+ T cells and γδ T cells. Our findings suggest that intestinal dysbiosis can alter γδ T cell activity. Treatment of mice with oral antibiotics significantly attenuates the clinical course of EAE induced by active immunization with MOG and CFA. This was reflected in a significant reduction in VLA-4, CCR6 and LFA-1 expression on T cells and infiltration of IL-17+, IFN-γ+ and IFN-γ+IL-17+ CD4 T cells into the CNS. However, T cell cytokine production in the periphery remained unchanged. Furthermore, depletion of the microbiome in recipient mice impaired the ability to induce EAE by transfer of pathogenic T cells from mice with a normal gut flora, suggesting that the microbiome plays a critical role in the migratory and encephalitogenic activity of T cells. Innate IL-1 plays a key role with IL-23 in activating IL-17-secreting γδ T cells that are pathogenic in EAE. Il1r1−/− mice are significantly more resistant to EAE than wild-type mice. Transfer of Vγ4+ γδ T cells from naive mice increased the susceptibility of Il1r1−/− mice to induction of EAE. In contrast, Vγ4 T cells from microbiome-depleted mice had limited ability to confer susceptibility to EAE in Il1r1−/− mice. Our findings demonstrate the microbiome is necessary to prime γδ T cells during induction of EAE and moreover, is required for the licensing of T cells to traffic from the periphery into the CNS.
This work was supported in part by grants provided by AbbVie.