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

WP Chong*, Panhuys N van, Jun Chen, Phyllis B Silver, Yingyos Jittayasothorn, Mary J. Mattapallil, Ronald N. Germain, Rachel R. Caspi*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

61 Citations (Scopus)


IFN-γ is a pathogenic cytokine involved in inflammation. Paradoxically, its deficiency exacerbates experimental autoimmune encephalomyelitis, uveitis, and arthritis. Here, we demonstrate using IFN-γ(-/-) mice repleted with IFN-γ +/+: NK cells that innate production of IFN-γ from NK cells is necessary and sufficient to trigger an endogenous regulatory circuit that limits autoimmunity. After immunization, 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. Our data reveal that an early NK-DC interaction controls the adaptive Th17 response and limits tissue-specific autoimmunity through an innate IFN-γ-IL-27 axis.
Original languageEnglish
Pages (from-to)1739-1752
JournalThe Journal of experimental medicine
Issue number10
Publication statusPublished - 7 Sept 2015


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