title: KIR2DL3 and KIR2DL1 show similar impact on licensing of human NK cells.
abstract: Killer cell immunoglobulin-like receptor/HLA class I (KIR/HLA-I) combinations are associated with disease risk, implicating functional roles for NK cells (NKCs) or KIR(+) T cells. KIR/HLA-I interactions can act through inhibition of NKC activation by target cells and NKC licensing for greater intrinsic responsiveness. We compared licensing conferred by the weaker, HLA-C group 1/KIR2DL3, and the stronger, HLA-C group 2/KIR2DL1, inhibitory combinations. The "rheostat model" predicts weaker licensing by HLA-C1/KIR2DL3 interactions than HLA-C2/KIR2DL1. We analyzed degranulation in NKC subsets expressing single and multiple receptors for HLA-I. NKG2A had the strongest licensing impact, while KIR2DL3, KIR2DL1, and KIR3DL1 were weaker, and not significantly different to each other. Presence of one or two matched HLA-C allotypes did not alter licensing of KIR2DL3(+) and KIR2DL1(+) NKC. Coexpression of activating KIR2DS1 disarmed KIR2DL3(+) and KIR2DL1(+) NKC to a similar extent. KIR3DL1 and NKG2A combined for more enhanced licensing of double-positive NKC than the combination of KIR2DL3 and KIR2DL1. Thus, KIR2DL3 and KIR2DL1 have similar capacity to license NKC, suggesting that inhibitory signal strength and amount of available HLA-C ligands do not correlate with NKC licensing. Altogether, our results show that the basis for disease associations of HLA-C and KIR2DL likely encompasses factors other than licensing.
authors.affiliation: Lung Immunology Group, Infectious Diseases and Immunity, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK.|Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
authors.forename: Malcolm J W
authors.initials: MJ
authors.lastname: Sim
authors.affiliation: Lung Immunology Group, Infectious Diseases and Immunity, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Janet
authors.initials: J
authors.lastname: Stowell
authors.affiliation: Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK.
authors.forename: Ruhena
authors.initials: R
authors.lastname: Sergeant
authors.affiliation: Lung Immunology Group, Infectious Diseases and Immunity, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Altmann
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Long
authors.affiliation: Lung Immunology Group, Infectious Diseases and Immunity, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Rosemary J
authors.initials: RJ
authors.lastname: Boyton
mesh_terms: D005434:Flow Cytometry; D015236:HLA-C Antigens / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000276:immunology*; D054342:Receptors, KIR2DL1 / Q000276:immunology*; D054344:Receptors, KIR2DL3 / Q000276:immunology*
chemical_list: D015236:HLA-C Antigens; C093100:KIR2DL1 protein, human; C515078:KIR2DL3 protein, human; D054342:Receptors, KIR2DL1; D054344:Receptors, KIR2DL3
keywords: Human leukocyte antigen (HLA); Killer immunoglobulin-like receptor (KIR); Licensing; NK cell (NKC); Rheostat model