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Rachel R Caspi, Nicholas van Panhuys, Jun Chen, Phyllis Silver, Yingyos Jittayasothorn, Ronald N Germain, Wai Po Chong; NK-DC crosstalk controls the autopathogenic Th17 response and suppresses uveitis through an innate IFN-γ/IL-27 axis. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3207.
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IFN-γ is a pathogenic cytokine involved in inflammation. Paradoxically, its deficiency exacerbates experimental autoimmune uveitis (EAU), encephalomyelitis, and arthritis. We have previously demonstrated that unlike adaptive IFN-γ produced by Th1 cells within the target tissue, innate IFN-γ produced systemically during the first days after immunization is protective. However, its cellular source and cellular target were unknown.
IFN-γ-/- mice have an amplified Th17 response and are highly susceptible to EAU. We used a reductionist system of IFN-γ-/- mice repleted with IFN-γ+/+ NK cells to study the role of NK cell-derived IFN-γ on EAU induced by uveitogenic immunization with IRBP. Fundoscopic examination, immunological assays and in vivo 2-photon imaging were used to examine disease development and the associated immune responses.
Following immunization for EAU, DCs recruited IFN-γ-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-γ 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.
We demonstrate that innate production of IFN-γ from NK cells is necessary and sufficient to trigger an endogenous regulatory circuit driven by an NK-DC interaction, which controls the adaptive Th17 response and limits tissue-specific autoimmunity though an innate IFN-γ/IL-27 axis.
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