NK-DC crosstalk controls the autopathogenic Th17 response through an innate IFN-?-IL-27 axis.

ABSTRACT: IFN-? is a pathogenic cytokine involved in inflammation. Paradoxically, its deficiency exacerbates experimental autoimmune encephalomyelitis, uveitis, and arthritis. Here, we demonstrate using IFN-?(-/-) mice repleted with IFN-? +/+: NK cells that innate production of IFN-? from NK cells is necessary and sufficient to trigger an endogenous regulatory circuit that limits autoimmunity. After immunization, DCs recruited IFN-?-producing NK cells to the draining lymph node and interacted with them in a CXCR3-dependent fashion. The interaction caused DCs to produce IL-27, which in turn enhanced IFN-? production by NK cells, forming a self-amplifying positive feedback loop. IL-10, produced by the interacting cells themselves, was able to limit this process. The NK-DC-dependent IL-27 inhibited development of the adaptive pathogenic IL-17 response and induced IL-10-producing Tr1-like cells, which ameliorated disease in an IL-10-dependent manner. Our data reveal that an early NK-DC interaction controls the adaptive Th17 response and limits tissue-specific autoimmunity through an innate IFN-?-IL-27 axis.

SUBMITTER: Chong WP 

PROVIDER: S-EPMC4577839 | biostudies-other | 2015 Sep

REPOSITORIES: biostudies-other