TY - JOUR
T1 - NK-DC crosstalk controls the autopathogenic Th17 response through an innate IFN-γ-IL-27 axis
AU - Chong, WP
AU - van, Panhuys N
AU - Chen, Jun
AU - Silver, Phyllis B
AU - Jittayasothorn, Yingyos
AU - Mattapallil, Mary J.
AU - Germain, Ronald N.
AU - Caspi, Rachel R.
N1 - This work was supported by the Intramural Research Programs of the National Eye Institute and the National Institute of Allergy and Infectious Diseases, National Institutes of Health
PY - 2015/9/7
Y1 - 2015/9/7
N2 - 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.
AB - 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.
UR - http://europepmc.org/abstract/med/26347474
U2 - 10.1084/jem.20141678
DO - 10.1084/jem.20141678
M3 - Journal article
C2 - 26347474
SN - 0022-1007
VL - 212
SP - 1739
EP - 1752
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 10
ER -