IL-17A controls CNS autoimmunity by regulating gut microbiota and inducing regulatory T cells

Shahi, S. K.; Ghimire, S.; Jensen, S. N.; Lehman, P.; Borcherding, N.; Gibson-Corley, K.; Ganesan, S. M.; Karandikar, N. J.; Mangalam, A. K.

doi:10.1101/2022.04.22.489206

bioRxiv · 10.1101/2022.04.22.489206

IL-17A controls CNS autoimmunity by regulating gut microbiota and inducing regulatory T cells

Shahi, S. K.·Ghimire, S.·Jensen, S. N.·Lehman, P.·Borcherding, N.·Gibson-Corley, K.·Ganesan, S. M.·Karandikar, N. J.·Mangalam, A. K.

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Abstract

A disrupted equilibrium among gut microbiota, IL-17A-producing CD4 T-cells (Th17), and regulatory CD4 T-cells (Treg) have been linked with the pathobiology of multiple sclerosis (MS). While gut microbiota can regulate both Treg and Th17 cells, the impact of IL-17A on this gut-immune connection remains unclear. Utilizing HLA-DR3 transgenic mouse model of MS, we show that IL-17A deficiency (HLA-DR3.IL17A-/-) resulted in milder disease characterized by increased Tregs and expansion of Treg-promoting gut microbes, including Prevotella. Cohousing HLA-DR3 mice with HLA-DR3.IL17A-/- transferred the milder disease phenotype and associated microbiota changes to DR3 mice, highlighting the dominant role of gut microbiota in Treg induction and disease amelioration. DR3.IL17A-/- mice also showed a higher abundance of functional pathways linked with short-chain fatty acid synthesis and elevated IL-10 in dendritic cells. Enrichment of the Treg-promoting PPAR signaling pathway expression in the colon of HLA-DR3.IL17A-/- mice and following Prevotella administration in HLA-DR3 mice underscores the importance of gut microbiota in IL-17A-mediated immune regulation. Thus, our study uncovers a previously unappreciated role for IL-17A in shaping gut microbiota and immune regulation, with far-reaching implications for MS treatment. One-Sentence SummaryIL-17A modulates Treg and gut microbiota to control EAE

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Shahi, S. K., Ghimire, S., Jensen, S. N., Lehman, P., Borcherding, N., Gibson-Corley, K., Ganesan, S. M., Karandikar, N. J., Mangalam, A. K.. 2022-04-22. IL-17A controls CNS autoimmunity by regulating gut microbiota and inducing regulatory T cells. https://doi.org/10.1101/2022.04.22.489206

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