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.

[1]  Antonio Lanzavecchia,et al.  Induced recruitment of NK cells to lymph nodes provides IFN-γ for TH1 priming , 2004, Nature Immunology.

[2]  Lewis L Lanier,et al.  NK cell recognition. , 2005, Annual review of immunology.

[3]  C. Barnstable,et al.  Use of a monoclonal antibody (W6/32) in structural studies of HLA-A,B,C, antigens. , 1979, Journal of immunology.

[4]  M. Carrington,et al.  Combinations of Maternal KIR and Fetal HLA-C Genes Influence the Risk of Preeclampsia and Reproductive Success , 2004, The Journal of experimental medicine.

[5]  A. Moretta.  Natural killer cells and dendritic cells: rendezvous in abused tissues , 2002, Nature Reviews Immunology.

[6]  R. Vance,et al.  Regulation of the natural killer cell receptor repertoire. , 2001, Annual review of immunology.

[7]  Eric O Long,et al.  Direct binding and functional transfer of NK cell inhibitory receptors reveal novel patterns of HLA-C allotype recognition. , 1998, Journal of immunology.

[8]  J. Orange.  Human natural killer cell deficiencies and susceptibility to infection. , 2002, Microbes and infection.

[9]  M. Mańczak,et al.  Gene for the activating natural killer cell receptor, KIR2DS1, is associated with susceptibility to psoriasis vulgaris. , 2004, Human immunology.

[10]  J. Strominger,et al.  Differential binding to HLA-C of p50-activating and p58-inhibitory natural killer cell receptors. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Eric O Long,et al.  The Direct Binding of a p58 Killer Cell Inhibitory Receptor to Human Histocompatibility Leukocyte Antigen (HLA)-Cw4 Exhibits Peptide Selectivity , 1997, The Journal of experimental medicine.

[12]  H. Ploegh,et al.  Monoclonal antibodies raised against denatured HLA-B locus heavy chains permit biochemical characterization of certain HLA-C locus products. , 1986, Journal of immunology.

[13]  E. Ciccone,et al.  General role of HLA class I molecules in the protection of target cells from lysis by natural killer cells: evidence that the free heavy chains of class I molecules are not sufficient to mediate the protective effect. , 1995, International immunology.

[14]  Jeffrey C. Boyington,et al.  Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand , 2000, Nature.

[15]  A. Plebani,et al.  HLA class I deficiencies due to mutations in subunit 1 of the peptide transporter TAP1. , 1999, The Journal of clinical investigation.

[16]  T. Sasazuki,et al.  Genetic polymorphisms of killer cell immunoglobulin-like receptors are associated with susceptibility to psoriasis vulgaris. , 2004, The Journal of investigative dermatology.

[17]  X. Saulquin,et al.  Crystal Structure of the Human Natural Killer Cell Activating Receptor KIR2DS2 (CD158j) , 2003, The Journal of experimental medicine.

[18]  S. Akira,et al.  TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. , 2004, Immunity.

[19]  Jonathan W. Heusel,et al.  Vital Involvement of a Natural Killer Cell Activation Receptor in Resistance to Viral Infection , 2001, Science.

[20]  S. Powis,et al.  Misfolding of Major Histocompatibility Complex Class I Molecules in Activated T Cells Allows cis-Interactions with Receptors and Signaling Molecules and Is Associated with Tyrosine Phosphorylation* , 2004, Journal of Biological Chemistry.

[21]  L. Lanier,et al.  Epistasis between mouse Klra and major histocompatibility complex class I loci is associated with a new mechanism of natural killer cell–mediated innate resistance to cytomegalovirus infection , 2005, Nature Genetics.

[22]  P. Parham.  MHC class I molecules and kirs in human history, health and survival , 2005, Nature Reviews Immunology.

[23]  L. Lanier,et al.  Cross-Talk between Activated Human NK Cells and CD4+ T Cells via OX40-OX40 Ligand Interactions1 , 2004, The Journal of Immunology.

[24]  Salim I. Khakoo,et al.  HLA and NK Cell Inhibitory Receptor Genes in Resolving Hepatitis C Virus Infection , 2004, Science.

[25]  Seung-Hwan Lee,et al.  Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily , 2001, Nature Genetics.

[26]  J. Strominger,et al.  Kinetics of interaction of HLA-C ligands with natural killer cell inhibitory receptors. , 1998, Immunity.

[27]  L. Moretta,et al.  Existence of both inhibitory (p58) and activatory (p50) receptors for HLA-C molecules in human natural killer cells , 1995, The Journal of experimental medicine.

[28]  L. Lanier,et al.  Direct Recognition of Cytomegalovirus by Activating and Inhibitory NK Cell Receptors , 2002, Science.

[29]  R. Biassoni,et al.  Role of amino acid position 70 in the binding affinity of p50.1 and p58.1 receptors for HLA‐Cw4 molecules , 1997, European journal of immunology.

[30]  D. Raulet.  Interplay of natural killer cells and their receptors with the adaptive immune response , 2004, Nature Immunology.

[31]  Michael J. Wilson,et al.  Cutting Edge: Leukocyte Receptor Complex-Encoded Immunomodulatory Receptors Show Differing Specificity for Alternative HLA-B27 Structures1 , 2001, The Journal of Immunology.

[32]  H. Achdout,et al.  MHC Class I-Independent Recognition of NK-Activating Receptor KIR2DS41 , 2004, The Journal of Immunology.

[33]  M. Smyth,et al.  Cross-talk between dendritic cells and natural killer cells in viral infection. , 2005, Molecular immunology.

[34]  P. Parham,et al.  Natural selection drives recurrent formation of activating killer cell immunoglobulin-like receptor and Ly49 from inhibitory homologues , 2005, The Journal of experimental medicine.

[35]  P. Parham,et al.  The HLA-A,B "negative" mutant cell line C1R expresses a novel HLA-B35 allele, which also has a point mutation in the translation initiation codon. , 1992, Journal of immunology.

[36]  Keith Hoots,et al.  Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS , 2002, Nature Genetics.

[37]  P. Sun,et al.  A structural perspective on MHC class I recognition by killer cell immunoglobulin-like receptors. , 2002, Molecular immunology.

[38]  H. Ljunggren,et al.  Selective rejection of H–2-deficient lymphoma variants suggests alternative immune defence strategy , 1986, Nature.

[39]  B. Koeleman,et al.  KIR in type 1 diabetes: disparate distribution of activating and inhibitory natural killer cell receptors in patients versus HLA-matched control subjects. , 2003, Diabetes.

[40]  B. Malissen,et al.  Structural and genetic analyses of HLA class I molecules using monoclonal xenoantibodies. , 2008, Tissue antigens.

[41]  L. Carayannopoulos,et al.  Recognition of infected cells by natural killer cells. , 2004, Current opinion in immunology.

[42]  O. Mandelboim,et al.  Recognition of HLA-Cw4 but Not HLA-Cw6 by the NK Cell Receptor Killer Cell Ig-Like Receptor Two-Domain Short Tail Number 41 , 2001, The Journal of Immunology.

[43]  M. Caligiuri,et al.  NK cell and DC interactions. , 2004, Trends in immunology.

[44]  Eric Vivier,et al.  Natural Killer Cell Signaling Pathways , 2004, Science.

[45]  H. Young,et al.  Human B Cell Activation by Autologous NK Cells Is Regulated by CD40-CD40 Ligand Interaction: Role of Memory B Cells and CD5+ B Cells , 2001, The Journal of Immunology.

[46]  D. Fremont,et al.  Recognition of a virus-encoded ligand by a natural killer cell activation receptor , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[47]  BIAcore analysis to test phosphopeptide-SH2 domain interactions. , 2000, Methods in molecular biology.

[48]  G. Lenoir,et al.  Gene Array Identification of Epstein Barr Virus-Regulated Cellular Genes in EBV-Converted Burkitt Lymphoma Cell Lines , 2002, Laboratory Investigation.

[49]  K. Hsu,et al.  The killer cell immunoglobulin‐like receptor (KIR) genomic region: gene‐order, haplotypes and allelic polymorphism , 2002, Immunological reviews.

[50]  G. Gao,et al.  Killer Cell Immunoglobulin Receptors and T Cell Receptors Bind Peptide-Major Histocompatibility Complex Class I with Distinct Thermodynamic and Kinetic Properties* , 1999, The Journal of Biological Chemistry.

[51]  Sumati Rajagopalan,et al.  Understanding how combinations of HLA and KIR genes influence disease , 2005, The Journal of experimental medicine.

[52]  D. Margulies,et al.  Structure and function of natural killer cell receptors: multiple molecular solutions to self, nonself discrimination. , 2002, Annual review of immunology.

[53]  B. Plougastel,et al.  Immune functions encoded by the natural killer gene complex , 2003, Nature Reviews Immunology.

[54]  J. Trowsdale,et al.  Restoration of endogenous antigen processing in Burkitt's lymphoma cells by Epstein‐Barr virus latent membrane protein‐1: coordinate up‐regulation of peptide transporters and HLA‐class I antigen expression , 1995, European journal of immunology.