IL-17 controls central nervous system autoimmunity through the intestinal 
microbiome

Regen, Tommy; Isaac, Sandrine; Amorim, Ana; Nunez, Nicolas Gonzalo; Hauptmann, Judith; Shanmugavadivu, Arthi; Klein, Matthias; Sankowski, Roman; Mufazalov, Ilgiz A.; Yogev, Nir; Huppert, Jula; Wanke, Florian; Witting, Michael; Grill, Alexandra; Galvez, Eric J. C.; Nikolaev, Alexei; Blanfeld, Michaela; Prinz, Immo; Schmitt-Kopplin, Philippe; Strowig, Till; Reinhardt, Christoph; Prinz, Marco; Bopp, Tobias; Becher, Burkhard; Ubeda, Carles; Waisman, Ari

doi:10.1126/sciimmunol.aaz6563

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IL-17 controls central nervous system autoimmunity through the intestinal microbiome

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Regen, T., Isaac, S., Amorim, A., Nunez, N. G., Hauptmann, J., Shanmugavadivu, A., et al. (2021). IL-17 controls central nervous system autoimmunity through the intestinal microbiome. Science Immunology, 6(56): eaaz6563. doi:10.1126/sciimmunol.aaz6563.

Cite as: https://hdl.handle.net/21.11116/0000-000A-B2AE-9

Abstract

Interleukin-17A- (IL-17A) and IL-17F-producing CD4(+) T helper cells (T(H)17 cells) are implicated in the development of chronic inflammatory diseases, such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). T-H 17 cells also orchestrate leukocyte invasion of the central nervous system (CNS) and subsequent tissue damage. However, the role of IL-17A and IL-17F as effector cytokines is still confused with the encephalitogenic function of the cells that produce these cytokines, namely, T-H 17 cells, fueling a long-standing debate in the neuroimmunology field. Here, we demonstrated that mice deficient for IL-17A/F lose their susceptibility to EAE, which correlated with an altered composition of their gut microbiota. However, loss of IL-17A/F in T-H cells did not diminish their encephalitogenic capacity. Reconstitution of a wild-type-like intestinal microbiota or reintroduction of IL-17A specifically into the gut epithelium of IL-17A/F-deficient mice reestablished their susceptibility to EAE. Thus, our data demonstrated that IL-17A and IL-17F are not encephalitogenic mediators but rather modulators of intestinal homeostasis that indirectly alter CNS-directed autoimmunity.