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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

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
Related URLs:
URLURL TypeDescription
http://jimmunol.org/cgi/content/meeting_abstract/190/1_MeetingAbstracts/136.13PublisherArticle
ORCID:
AuthorORCID
Lin, Lin0000-0001-6860-9566
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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