Recognition of peptide-MHC class I complexes by activating killer immunoglobulin-like receptors.
Inhibitory receptors for MHC class I molecules increase the threshold of lymphocyte activation. Natural Killer (NK) cells express a large number of such inhibitory receptors, including the human killer Ig-like receptors (KIR). However, activating members of the KIR family have poorly defined ligands and functions. Here we describe the use of activating KIR tetramer reagents as probes to detect their ligands. Infection of cells with Epstein-Barr virus leads to expression of a detectable ligand for the activating receptor KIR2DS1. In this case, KIR2DS1 interacts with up-regulated peptide-MHC class I complexes on Epstein-Barr virus-infected cells in a transporter associated with antigen processing (TAP)-dependent manner. In tetramer-based cellular assays and direct affinity measurements, this interaction with MHC class I is facilitated by a broad spectrum of peptides. KIR2DS1 and its inhibitory homologue, KIR2DL1, share sensitivity to peptide sequence alterations at positions 7 and 8. These results fit a model in which activating and inhibitory receptors recognize the same sets of self-MHC class I molecules, differing only in their binding affinities. Importantly, KIR2DS1 is not always sufficient to trigger NK effector responses when faced with cognate ligand, consistent with fine control during NK cell activation. We discuss how our results for KIR2DS1 and parallel studies on KIR2DS2 relate to the association between activating KIR genes and susceptibility to autoimmune disorders.
Stewart
C Andrew
CA
Centre d'Immunologie de Marseille-Luminy, Institut National de la Santé et de la Recherche Médicale-Centre National de la Recherche Scientifique-Université Méditerranée, 13288 Marseille Cedex 09, France. stewart@ciml.univ-mrs.fr
Laugier-Anfossi
Fanny
F
Vély
Frédéric
F
Saulquin
Xavier
X
Riedmuller
Jenifer
J
Tisserant
Agnès
A
Gauthier
Laurent
L
Romagné
François
F
Ferracci
Géraldine
G
Arosa
Fernando A
FA
Moretta
Alessandro
A
Sun
Peter D
PD
Ugolini
Sophie
S
Vivier
Eric
E
D018528:ATP-Binding Cassette Transporters; D001327:Autoimmune Diseases / Q000209:etiology; D006680:HLA Antigens / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000276:immunology* / Q000378:metabolism; D054340:Receptors, KIR; D054342:Receptors, KIR2DL1; D014764:Viral Proteins / Q000276:immunology
D018528:ATP-Binding Cassette Transporters; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; C093100:KIR2DL1 protein, human; C496212:KIR2DS1 protein, human; D008024:Ligands; D010446:Peptide Fragments; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D054342:Receptors, KIR2DL1; D014764:Viral Proteins; C477327:transporter associated with antigen processing (TAP)