Regen, TommyIsaac, SandrineAmorim, AnaNunez, Nicolas GonzaloHauptmann, JudithShanmugavadivu, ArthiKlein, MatthiasSankowski, RomanMufazalov, Ilgiz A.Yogev, NirHuppert, JulaWanke, FlorianWitting, MichaelGrill, AlexandraGalvez, Eric J. C.Nikolaev, AlexeiBlanfeld, MichaelaPrinz, ImmoSchmitt-Kopplin, PhilippeStrowig, TillReinhardt, ChristophPrinz, MarcoBopp, TobiasBecher, BurkhardUbeda, CarlesWaisman, Ari2021-03-262021-03-262021-03-262021-02-0110.1126/sciimmunol.aaz6563https://infoscience.epfl.ch/handle/20.500.14299/176865WOS:000616626200001Interleukin-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.Immunologygut microbiotat-cellsinterleukin-17cnsneutralizationsequencescytokinereceptortext::journal::journal article::research article