Lin, Lin and Ma, Chao and Wei, Bo and Rajalingam, Raja and Yusung, Susy and Trachtenberg, Elizabeth and Targan, Stephan and McGovern, Dermot and Braun, Jonathan (2013) Genetically-determined cytokine programs of human NK cells uncover a novel mechanism of NK cells and Killer cell IgG-like Receptor genes in Crohn's Disease susceptibility. Journal of Immunology, 190 . 136.13. ISSN 0022-1767. https://resolver.caltech.edu/CaltechAUTHORS:20130912-102144974
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Abstract
Mucosal innate lymphocyte subsets have emerged as an important new factor in CD pathogenesis, but the role of NK cells is poorly understood. A recent genetic study identified the KIR gene KIR2DL2/3 as a risk factor for CD in the genetic context of its ligand HLA-C1. However, the biologic mechanism of this genetic contribution is unknown. NK cells are mainly known for their cytolytic function, but recent work indicates that strong KIR/HLA interactions that induce NK "licensing" augment NK cytotoxicity but also IFN-γ production. We therefore tested the hypothesis that human NK licensing by KIR2DL2/3 and HLA-C1 induces a broader cytokine program that modifies the threshold of pro-inflammatory T cell activation. Single cell multiplex functional proteomics revealed that licensed and unlicensed NK cells had strikingly distinct cytokine programs. Licensed NK cells were distinguished by high-output, proinflammatory, poly-cytokine expression. Select cytokine among this output fully accounted for their unique capacity, unlike unlicensed NK cells, to efficiently augment antigenic CD4+ T cell proliferation and induce CD4+ T cell IL-17A production. In conclusion, NK licensing mediated by KIR2DL2/3 and HLA-C1 elicits a novel cytokine program of NK cells that activates and induces pro-inflammatory CD4+ T cells, and therefore provides a predisposing biologic mechanism for this KIR-associated susceptibility to CD and other chronic inflammatory syndromes.
Item Type: | Article | ||||||
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Additional Information: | © 2013 American Association of Immunologists. | ||||||
Record Number: | CaltechAUTHORS:20130912-102144974 | ||||||
Persistent URL: | https://resolver.caltech.edu/CaltechAUTHORS:20130912-102144974 | ||||||
Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | ||||||
ID Code: | 41283 | ||||||
Collection: | CaltechAUTHORS | ||||||
Deposited By: | Tony Diaz | ||||||
Deposited On: | 12 Sep 2013 22:48 | ||||||
Last Modified: | 09 Mar 2020 13:19 |
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