{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:44:21Z","timestamp":1791290661632,"version":"4.3.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2014,7,1]],"date-time":"2014-07-01T00:00:00Z","timestamp":1404172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u2019s disease (CD), a chronic intestinal inflammatory disease. However, the cellular mechanism of this genetic contribution is unknown. In this study, we show that the \u201clicensing\u201d 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-\u03b3, TNF-\u03b1, CCL-5, and MIP-1\u03b2. Cytokines produced by licensed NK augmented CD4+ T cell proliferation and IL-17A\/IL-22 production. Ab blocking indicated a primary role for IFN-\u03b3, TNF-\u03b1, and IL-6 in the augmented T cell\u2013proliferative 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.<\/jats:p>","DOI":"10.4049\/jimmunol.1400093","type":"journal-article","created":{"date-parts":[[2014,6,17]],"date-time":"2014-06-17T02:54:25Z","timestamp":1402973665000},"page":"940-949","source":"Crossref","is-referenced-by-count":35,"title":["Human NK Cells Licensed by Killer Ig Receptor Genes Have an Altered Cytokine Program That Modifies CD4+ T Cell Function"],"prefix":"10.1093","volume":"193","author":[{"given":"Lin","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California , Los Angeles, Los Angeles, CA 90095"},{"name":"Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California , Los Angeles, Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Ma","sequence":"additional","affiliation":[{"name":"Division of Physics, Mathematics and Astronomy, California Institute of Technology , Pasadena, CA 91125"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California , Los Angeles, Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Najib","family":"Aziz","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California , Los Angeles, Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raja","family":"Rajalingam","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California , Los Angeles, Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susy","family":"Yusung","sequence":"additional","affiliation":[{"name":"Mattel Children's Hospital, David Geffen School of Medicine, University of California , Los Angeles, Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry A","family":"Erlich","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital Oakland Research Institute , Oakland, CA 94609"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A","family":"Trachtenberg","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University School of Medicine , Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan R","family":"Targan","sequence":"additional","affiliation":[{"name":"Translational Genomics Group, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute , Los Angeles, CA 90048"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dermot P B","family":"McGovern","sequence":"additional","affiliation":[{"name":"Translational Genomics Group, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute , Los Angeles, CA 90048"},{"name":"Medical Genetics Institute, Cedars-Sinai Medical Center , Los Angeles, CA 90048"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James R","family":"Heath","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California , Los Angeles, Los Angeles, CA 90095"},{"name":"NanoSystems Biology Cancer Center, California Institute of Technology , Pasadena, CA 91125"},{"name":"Division of Chemistry and Chemical Engineering, California Institute of Technology , Pasadena, CA 91125"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Braun","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California , Los Angeles, Los Angeles, CA 90095"},{"name":"Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California , Los Angeles, Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,7,15]]},"reference":[{"key":"2025030707243982000_r1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/B978-0-12-387664-5.00002-9","article-title":"Transcriptional control of natural killer cell development and function","volume":"109","author":"Hesslein","year":"2011","journal-title":"Adv. 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The example of natural killer cells","volume":"331","author":"Vivier","year":"2011","journal-title":"Science"},{"key":"2025030707243982000_r5","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1146\/annurev-immunol-031210-101332","article-title":"HLA\/KIR restraint of HIV: surviving the fittest","volume":"29","author":"Bashirova","year":"2011","journal-title":"Annu. Rev. Immunol."},{"key":"2025030707243982000_r6","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1111\/j.1600-065X.2006.00459.x","article-title":"KIR and disease: a model system or system of models?","volume":"214","author":"Khakoo","year":"2006","journal-title":"Immunol. 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