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Human NK Cells Licensed by Killer Ig Receptor Genes Have an Altered Cytokine Program That Modifies CD4+ T Cell Function

Lin, Lin and Ma, Chao and Wei, Bo and Aziz, Najib and Rajalingam, Raja and Yusung, Susy and Erlich, Henry A. and Trachtenberg, Elizabeth A. and Targan, Stephan R. and McGovern, Dermot P. B. and Heath, James R. and Braun, Jonathan (2014) Human NK Cells Licensed by Killer Ig Receptor Genes Have an Altered Cytokine Program That Modifies CD4+ T Cell Function. Journal of Immunology, 193 (2). pp. 940-949. ISSN 0022-1767. PMCID PMC4096688. https://resolver.caltech.edu/CaltechAUTHORS:20140623-090712146

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Abstract

NK cells are innate immune cells known for their cytolytic activities toward tumors and infections. They are capable of expressing diverse killer Ig-like receptors (KIRs), and KIRs are implicated in susceptibility to Crohn’s disease (CD), a chronic intestinal inflammatory disease. However, the cellular mechanism of this genetic contribution is unknown. In this study, we show that the “licensing” of NK cells, determined by the presence of KIR2DL3 and homozygous HLA-C1 in host genome, results in their cytokine reprogramming, which permits them to promote CD4+ T cell activation and Th17 differentiation ex vivo. Microfluidic analysis of thousands of NK single cells and bulk secretions established that licensed NK cells are more polarized to proinflammatory cytokine production than unlicensed NK cells, including production of IFN-γ, TNF-α, CCL-5, and MIP-1β. Cytokines produced by licensed NK augmented CD4+ T cell proliferation and IL-17A/IL-22 production. Ab blocking indicated a primary role for IFN-γ, TNF-α, and IL-6 in the augmented T cell–proliferative response. In conclusion, NK licensing mediated by KIR2DL2/3 and HLA-C1 elicits a novel NK cytokine program that activates and induces proinflammatory CD4+ T cells, thereby providing a potential biologic mechanism for KIR-associated susceptibility to CD and other chronic inflammatory diseases.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.4049/jimmunol.1400093DOIArticle
http://www.jimmunol.org/content/193/2/940.longPublisherArticle
http://www.jimmunol.org/lookup/suppl/doi:10.4049/jimmunol.1400093/-/DCSupplementalPublisherData Supplement
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096688/PubMed CentralArticle
ORCID:
AuthorORCID
Lin, Lin0000-0001-6860-9566
Heath, James R.0000-0001-5356-4385
Additional Information:© 2014 The American Association of Immunologists, Inc. Received January 16, 2014; Accepted May 15, 2014. Published online before print June 16, 2014. This work was supported by National Institutes of Health Grants PO1DK46763 (to S.R.T., D.P.B.M., and J.B.), CA119347 (to J.R.H.), 5 UO1 AI067068 (to H.A.E., E.A.T., and D.P.B.M.), DK062413 and DK046763-19 (to D.P.B.M.), and UL1TR000124 (to S.R.T., D.P.B.M., and J.B.) and the Cedars-Sinai F. Widjaja Inflammatory Bowel and Immunobiology Institute Research Fund. Project investigators were supported by the Helmsley Charitable Trust (to D.P.B.M.) and the European Union (to D.P.B.M.). This research was performed with material support provided by the Immune Tolerance Network, an international clinical research consortium headquartered at the University of California, San Francisco, and supported by the National Institute of Allergy and Infectious Diseases and the Juvenile Diabetes Research Foundation.
Funders:
Funding AgencyGrant Number
NIHPO1DK46763
NIHCA119347
NIH5 UO1 AI067068
NIHDK062413
NIHDK046763-19
NIHUL1TR000124
Cedars-Sinai F. Widjaja Inflammatory Bowel and Immunobiology Institute Research FundUNSPECIFIED
Helmsley Charitable TrustUNSPECIFIED
European UnionUNSPECIFIED
Immune Tolerance NetworkUNSPECIFIED
National Institute of Allergy and Infectious DiseasesUNSPECIFIED
Juvenile Diabetes Research FoundationUNSPECIFIED
Issue or Number:2
PubMed Central ID:PMC4096688
Record Number:CaltechAUTHORS:20140623-090712146
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20140623-090712146
Official Citation:Human NK Cells Licensed by Killer Ig Receptor Genes Have an Altered Cytokine Program That Modifies CD4+ T Cell Function Lin Lin, Chao Ma, Bo Wei, Najib Aziz, Raja Rajalingam, Susy Yusung, Henry A. Erlich, Elizabeth A. Trachtenberg, Stephan R. Targan, Dermot P. B. McGovern, James R. Heath, and Jonathan Braun J Immunol 2014 193:940-949; published ahead of print June 16, 2014, doi:10.4049/jimmunol.1400093
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:46426
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:23 Jun 2014 19:47
Last Modified:09 Mar 2020 13:19

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