Investigating the requirement of IL-17A and IFNg in EAE disease development using HLA-DR3.IL-17A^-/-.IFNg^-/- transgenic mice

Abstract Multiple sclerosis (MS), an autoimmune disease of the central nervous system, is thought to be mediated by autoreactive CD4+ T cells producing IL-17A and IFNg. However, it is unclear if these cytokines are essential for disease development, progression, or both. We have shown that neither IFNg nor IL-17A, alone, are required for the development of disease in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, but the absence of either results in different disease phenotypes. Specifically, HLA-DR3(DRB1*0301) (DR3).IFNg−/− mice develop severe atypical EAE characterized by increased levels of IL-17A, while DR3.IL-17A−/− mice develop mild, classical EAE. These data suggest that these cytokines may have compensatory roles. To further investigate the roles of these cytokines in EAE, we generated HLA-DR3.IFNg−/−.IL-17A−/− double knockout (DKO) mice and characterized their immune profiles, gut microbiomes, and disease phenotype. Our data show that DKO mice harbor distinct myeloid and CD4+ T cell profiles, myelin antigen-specific immune responses, and gut microbiota. Interestingly, DKO mice develop atypical EAE mimicking the disease phenotype of IFNg−/− mice. Thus, our data suggest that factors other than IL-17A and IFNg mediate atypical EAE susceptibility. Further characterizations of disease are ongoing in DKO mice to better define the precise roles of IL-17A and IFNg in the pathology of MS/EAE. NIAID/NIH (1R01AI137075-01) and a generous gift from Margaret Heppelmann and Michael Wacek.