title: NK Cell Proliferation Induced by IL-15 Transpresentation Is Negatively Regulated by Inhibitory Receptors.
abstract: IL-15 bound to the IL-15Rα-chain (IL-15Rα) is presented in trans to cells bearing the IL-2Rβ-chain and common γ-chain. As IL-15 transpresentation occurs in the context of cell-to-cell contacts, it has the potential for regulation by and of other receptor-ligand interactions. In this study, human NK cells were tested for the sensitivity of IL-15 transpresentation to inhibitory receptors. Human cells expressing HLA class I ligands for inhibitory receptors KIR2DL1, KIR2DL2/3, or CD94-NKG2A were transfected with IL-15Rα. Proliferation of primary NK cells in response to transpresented IL-15 was reduced by engagement of either KIR2DL1 or KIR2DL2/3 by cognate HLA-C ligands. Inhibitory KIR-HLA-C interactions did not reduce the proliferation induced by soluble IL-15. Therefore, transpresentation of IL-15 is subject to downregulation by MHC class I-specific inhibitory receptors. Similarly, proliferation of the NKG2A(+) cell line NKL induced by IL-15 transpresentation was inhibited by HLA-E. Coengagement of inhibitory receptors, either KIR2DL1 or CD94-NKG2A, did not inhibit phosphorylation of Stat5 but inhibited selectively phosphorylation of Akt and S6 ribosomal protein. IL-15Rα was not excluded from, but was evenly distributed across, inhibitory synapses. These findings demonstrate a novel mechanism to attenuate IL-15-dependent NK cell proliferation and suggest that inhibitory NK cell receptors contribute to NK cell homeostasis.
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; and.
authors.forename: Olga M
authors.initials: OM
authors.lastname: Anton
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; and.
authors.forename: Susina
authors.initials: S
authors.lastname: Vielkind
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; and.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Peterson
authors.affiliation: Division of Basic Science and Vaccine Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tagaya
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; and eLong@nih.gov.
authors.forename: Eric O
authors.identifier: http://orcid.org/0000-0002-7793-3728
authors.initials: EO
authors.lastname: Long
mesh_terms: D049109:Cell Proliferation / Q000502:physiology*; D005260:Female; D015236:HLA-C Antigens / Q000276:immunology; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology*; D053646:Interleukin-2 Receptor beta Subunit / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008297:Male; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000276:immunology*; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000276:immunology*; D010766:Phosphorylation / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D053647:Receptors, Interleukin-15 / Q000276:immunology; D054342:Receptors, KIR2DL1 / Q000276:immunology*; D054343:Receptors, KIR2DL2 / Q000276:immunology; D054344:Receptors, KIR2DL3 / Q000276:immunology
chemical_list: D015236:HLA-C Antigens; C569274:IL15 protein, human; C508024:IL15RA protein, human; C508020:IL2RB protein, human; D019409:Interleukin-15; D053646:Interleukin-2 Receptor beta Subunit; C093100:KIR2DL1 protein, human; C515077:KIR2DL2 protein, human; C515078:KIR2DL3 protein, human; C497869:KLRD1 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D053647:Receptors, Interleukin-15; D054342:Receptors, KIR2DL1; D054343:Receptors, KIR2DL2; D054344:Receptors, KIR2DL3; D051057:Proto-Oncogene Proteins c-akt