title: Human NK cells licensed by killer Ig receptor genes have an altered cytokine program that modifies CD4+ T cell function.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095;
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.affiliation: Division of Physics, Mathematics and Astronomy, California Institute of Technology, Pasadena, CA 91125;
authors.forename: Chao
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095;
authors.forename: Bo
authors.initials: B
authors.lastname: Wei
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095;
authors.forename: Najib
authors.initials: N
authors.lastname: Aziz
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095;
authors.forename: Raja
authors.initials: R
authors.lastname: Rajalingam
authors.affiliation: Mattel Children's Hospital, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095;
authors.forename: Susy
authors.initials: S
authors.lastname: Yusung
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA 94609;
authors.forename: Henry A
authors.initials: HA
authors.lastname: Erlich
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Trachtenberg
authors.affiliation: Translational Genomics Group, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, CA 90048;
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Targan
authors.affiliation: Translational Genomics Group, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, CA 90048; Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
authors.forename: Dermot P B
authors.initials: DP
authors.lastname: McGovern
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095; NanoSystems Biology Cancer Center, California Institute of Technology, Pasadena, CA 91125; and Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125.
authors.forename: James R
authors.initials: JR
authors.lastname: Heath
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095; JBraun@mednet.ucla.edu.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Braun
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016000:Cluster Analysis; D018920:Coculture Techniques; D003424:Crohn Disease / Q000097:blood / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000145:classification / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D015236:HLA-C Antigens / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D054340:Receptors, KIR / Q000276:immunology* / Q000378:metabolism; D054344:Receptors, KIR2DL3 / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D016207:Cytokines; D015236:HLA-C Antigens; D007371:Interferon-gamma; D020381:Interleukin-17; D015850:Interleukin-6; D007378:Interleukins; D054340:Receptors, KIR; D054344:Receptors, KIR2DL3; D014409:Tumor Necrosis Factor-alpha; D000097043:Interleukin-22; C515078:KIR2DL3 protein, human