title: Education of human natural killer cells by activating killer cell immunoglobulin-like receptors.
abstract: Expression of inhibitory killer cell immunoglobulin-like receptors (KIRs) specific for self-major histocompatibility complex (MHC) class I molecules provides an educational signal that generates functional natural killer (NK) cells. However, the effects of activating KIRs specific for self-MHC class I on NK-cell education remain elusive. Here, we provide evidence that the activating receptor KIR2DS1 tunes down the responsiveness of freshly isolated human NK cells to target cell stimulation in donors homozygous for human leukocyte antigen (HLA)-C2, the ligand of KIR2DS1. The tuning was apparent in KIR2DS1(+) NK cells lacking expression of inhibitory KIRs and CD94/NKG2A, as well as in KIR2DS1(+) NK cells coexpressing the inhibitory MHC class I-specific receptors CD94/NKG2A and KIR2DL3, but not KIR2DL1. However, the tuning of responsiveness was restricted to target cell recognition because KIR2DS1(+) NK cells responded well to stimulation with exogenous cytokines. Our results provide the first example of human NK-cell education by an activating KIR and suggest that the education of NK cells via activating KIRs is a mechanism to secure tolerance that complements education via inhibitory KIRs.
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Cyril
authors.initials: C
authors.lastname: Fauriat
authors.forename: Martin A
authors.initials: MA
authors.lastname: Ivarsson
authors.forename: Hans-Gustaf
authors.initials: HG
authors.lastname: Ljunggren
authors.forename: Karl-Johan
authors.initials: KJ
authors.lastname: Malmberg
authors.forename: Jakob
authors.initials: J
authors.lastname: Michaëlsson
mesh_terms: D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005434:Flow Cytometry; D015236:HLA-C Antigens / Q000235:genetics / Q000378:metabolism*; D006720:Homozygote; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism; D019409:Interleukin-15 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000235:genetics / Q000378:metabolism*; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054340:Receptors, KIR / Q000235:genetics / Q000378:metabolism*; D054344:Receptors, KIR2DL3 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015236:HLA-C Antigens; D019409:Interleukin-15; C515078:KIR2DL3 protein, human; C496212:KIR2DS1 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D012333:RNA, Messenger; D054340:Receptors, KIR; D054344:Receptors, KIR2DL3; D018664:Interleukin-12