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

Wai Po Chong, Nicholas J. Van Panhuys, Jun Chen, Phyllis B. Silver, Yingyos Jittayasothorn, Mary J. Mattapallil, Ronald N. Germain, Rachel R. Caspi

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30 Citations (Scopus)

Abstract

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 tissuespecific autoimmunity through an innate IFN-γ-IL-27 axis.

Original languageEnglish
Pages (from-to)1739-1752
Number of pages14
JournalJournal of Experimental Medicine
Volume212
Issue number10
DOIs
Publication statusPublished - 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Chong, W. P., Van Panhuys, N. J., Chen, J., Silver, P. B., Jittayasothorn, Y., Mattapallil, M. J., Germain, R. N., & Caspi, R. R. (2015). NK-DC crosstalk controls the autopathogenic Th17 response through an innate IFN-γ-IL-27 axis. Journal of Experimental Medicine, 212(10), 1739-1752. https://doi.org/10.1084/jem.20141678