NK-DC crosstalk controls the autopathogenic Th17 response through an innate IFN-γ-IL-27 axis.
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.
Laboratory of Immunology, National Eye Institute, Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 rcaspi@helix.nih.gov waipoc@mail.nih.gov.
Wai Po
WP
Chong
Laboratory of Immunology, National Eye Institute, Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Nicholas
N
van Panhuys
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmical Center, Sun Yat-sen University, Guangzhou 510060, China Laboratory of Immunology, National Eye Institute, Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Jun
J
Chen
Laboratory of Immunology, National Eye Institute, Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Phyllis B
PB
Silver
Laboratory of Immunology, National Eye Institute, Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Yingyos
Y
Jittayasothorn
Laboratory of Immunology, National Eye Institute, Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Mary J
MJ
Mattapallil
Laboratory of Immunology, National Eye Institute, Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Ronald N
RN
Germain
Laboratory of Immunology, National Eye Institute, Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 rcaspi@helix.nih.gov waipoc@mail.nih.gov.
Rachel R
RR
Caspi
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D025461:Feedback, Physiological; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology*; D014605:Uveitis / Q000276:immunology* / Q000473:pathology
C515188:Cxcr3 protein, mouse; C556062:IL10 protein, mouse; C486767:Il27 protein, mouse; D007378:Interleukins; D054367:Receptors, CXCR3; D016753:Interleukin-10; D007371:Interferon-gamma