Reciprocal interaction between NK cells and DCs regulates the Th17 response by controlling the innate IFN-γ/IL-27 axis (P4067)

Abstract

Abstract Experimental autoimmune uveitis (EAU) is a model for human uveitis. IFN-γ deficient mice develop enhanced EAU with elevated Th17 responses. This protective effect of IFN-γ appears at odds with the ability of IFN-γ-producing Th1 cells to induce EAU. We previously showed that it is innate IFN-γ that is protective, whereas adaptive IFN-γ is pathogenic. We now demonstrate that NK cells, a major cellular source of innate IFN-γ, interact with DCs in draining lymph nodes of EAU-challenged mice to ameliorate disease by controlling the innate IFN-γ/IL-27 axis. After immunization, both NK cells and DCs were recruited to the draining lymph nodes, with recruitment of NK cells being at least partially dependent on DCs and CXCR3. Infusion of IFN-γ-sufficient WT NK cells into IFN-γ-/- recipients reduced their EAU scores and enhanced production of IL 27, a suppressor of the Th17 response, from DCs of these mice. In vivo neutralization of IL-27 abolished the protective effect of WT NK cells on EAU. In vitro experiments revealed that mature DCs induced NK cells to produce IFN-γ, which in turn caused DCs to produce IL-27. IL-27 then stimulated NK cells to produce more IFN-γ, suggesting the presence of a positive feedback loop. IL-27 also promoted generation of IL-10-producing Tr1-like cells. Our results suggest that the magnitude of the Th17 response, and consequently the severity of disease, is controlled by the interaction between NK cells and DCs through the IFN-γ/IL-27 axis.