Multiple sclerosis (MS) is thought to be mediated by HLA class-II restricted autoreactive CD4+ T cells producing IL-17A and/or IFN, but whether one or both are required for disease pathogenesis is unknown. Utilizing HLA-DR3 (DRB1*0301) transgenic mice lacking IFN or IL-17A, we showed that neither is necessary for disease induction; however, both have distinct effects on disease. The absence of IFN results in atypical, brain-specific EAE and increased levels of IL-17A. However, the lack of IL-17A results in a classical, spinal cord-specific EAE with increased frequency/function of Treg cells and an enrichment of Treg-inducing gut microbiota. These data suggest that IL-17A and IFNγ are compensating for each other. Therefore, we hypothesized that HLA-DR3.IFN-/-.IL-17A-/- double knockout (DKO) mice would be resistant to EAE disease development. We observed atypical EAE in DKO mice, characterized by inflammation, demyelination, and CD45+ cell infiltration in the brainstem and cerebellum. DKO mice also have an upregulation of genes associated with Th17 differentiation and monocyte activation in the brain at peak disease incidence (40 days post immunization). We further hypothesized that DKO mice have unique CD4 T cell activation, differentiation, and effector functions in the secondary lymphoid organs (SLO) that contribute to atypical EAE disease. Our ex vivo analyses of lymphocytes from SLOs showed that DKO mice have significantly more CD4 T cell recruitment, CD4+RORgT+ T cells, and CD4+FoxP3+ T cells at 10 days post immunization. Our data suggest that factors other than IFN and IL-17A are required EAE susceptibility. Future studies aim to further elucidate if atypical EAE manifests due to CD4 T cell intrinsic or extrinsic factors. 

Publications:

Turner TA, Lehman P, Ghimire S, Shahi SK, Mangalam A. Game of microbes: the battle within - gut microbiota and multiple sclerosis. Gut Microbes. 2024;16(1):2387794. doi:10.1080/19490976.2024.2387794

The Role of the Gut Microbiome in Neurological Diseases. TAJ Turner, AK Mangalam. Elsevier. European Encyclopedia of the Neurological Sciences. (2024)

Investigating the requirement of IL-17A and IFNg in EAE disease development using HLA-DR3.IL-17A-/-IFNg-/- transgenic mice. TAJ Turner, S Peterson, S Shahi, AK Mangalam. The Journal of Immunology 210 (1_Supplement), 170.04-170.04 (2022)

Honors and Awards

Selected as Student Highlight for the Dare to Discover Campaign at the University of Iowa (2023)

Passed PhD Candidacy Comprehensive Examination (2023)

Recipient of an AAI 2023 Trainee Poster Award American Association of Immunologists 2023 (D.C.) (2023)

Recipient of the Legend in the Making Award at the 2022 Rosa Parks Gala hosted by the Southern Youth Leadership Development Institute (2022)

Recipient of National MS Society Travel Award at The Autumn Immunology Conference (2022)