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2DL1, 2DL2 and 2DL3 all contribute to KIR phenotype variability on human NK cells

Genes & Immunity volume 16, pages 301–310 (2015)Cite this article

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Abstract

Natural killer (NK) cells are lymphocytes that function as part of the innate immune system. Their activity is controlled by a range of inhibitory and activating receptors, including the important killer-cell immunoglobulin-like receptors (KIR). The KIR are a multi-gene family of receptors that interact with the human leukocyte antigen (HLA) class I family of molecules and are characterised by extensive allelic polymorphism. Their expression on the cell surface of NK cells is highly variable, but the factors responsible for this variability are not yet clearly understood. In the current study, we investigated KIR expression in a healthy human cohort that we had previously characterised in depth at a genetic level, with KIR allele typing and HLA class I ligand genotypes available for all donors (n=198). Allelic polymorphism significantly affected the phenotypic expression of all KIR analysed, whereas HLA ligand background influenced the expression levels of 2DL1 and 2DL3. In particular, we found that although 2DL2 may influence 2DL1 expression, this appears to be owing to variation in 2DL1 copy number. Finally, the inhibitory receptor LILRB1 had higher expression levels in individuals with B/B KIR genotypes, suggesting a possible relationship between KIR and non-KIR receptors, which serves to balance NK cell activation potential.

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References

  1. O'Connor GM, Hart OM, Gardiner CM . Putting the natural killer cell in its place. Immunology 2006; 117: 1–10.

    Article  CAS  Google Scholar 

  2. Cerwenka A, Lanier LL . Natural killer cells, viruses and cancer. Nat Rev Immunol 2001; 1: 41–49.

    Article  CAS  Google Scholar 

  3. Vilches C, Parham P . KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu Rev Immunol 2002; 20: 217–251.

    Article  CAS  Google Scholar 

  4. Robinson J, Waller MJ, Stoehr P, Marsh SG . IPD—the immuno polymorphism database. Nucleic Acids Res 2005; 33 Database issue D523–D526.

    Article  CAS  Google Scholar 

  5. Gardiner CM, Guethlein LA, Shilling HG, Pando M, Carr WH, Rajalingam R et al. Different NK cell surface phenotypes defined by the DX9 antibody are due to KIR3DL1 gene polymorphism. J Immunol 2001; 166: 2992–3001.

    Article  CAS  Google Scholar 

  6. Gagne K, Willem C, Legrand N, Djaoud Z, David G, Rettman P et al. Both the nature of KIR3DL1 alleles and the KIR3DL1/S1 allele combination affect the KIR3DL1 NK-cell repertoire in the French population. Eur J Immunol 2013; 43: 1085–1098.

    Article  CAS  Google Scholar 

  7. Thomas R, Yamada E, Alter G, Martin MP, Bashirova AA, Norman PJ et al. Novel KIR3DL1 alleles and their expression levels on NK cells: convergent evolution of KIR3DL1 phenotype variation? J Immunol 2008; 180: 6743–6750.

    Article  CAS  Google Scholar 

  8. Goodridge JP, Lathbury LJ, Steiner NK, Shulse CN, Pullikotil P, Seidah NG et al. Three common alleles of KIR2DL4 (CD158d) encode constitutively expressed, inducible and secreted receptors in NK cells. Eur J Immunol 2007; 37: 199–211.

    Article  CAS  Google Scholar 

  9. Goodridge JP, Witt CS, Christiansen FT, Warren HS . KIR2DL4 (CD158d) genotype influences expression and function in NK cells. J Immunol 2003; 171: 1768–1774.

    Article  CAS  Google Scholar 

  10. Middleton D, Gonzalez A, Gilmore PM . Studies on the expression of the deleted KIR2DS4*003 gene product and distribution of KIR2DS4 deleted and nondeleted versions in different populations. Hum Immunol 2007; 68: 128–134.

    Article  CAS  Google Scholar 

  11. Yawata M, Yawata N, Draghi M, Little AM, Partheniou F, Parham P . Roles for HLA and KIR polymorphisms in natural killer cell repertoire selection and modulation of effector function. J Exp Med 2006; 203: 633–645.

    Article  CAS  Google Scholar 

  12. Schonberg K, Sribar M, Enczmann J, Fischer JC, Uhrberg M . Analyses of HLA-C-specific KIR repertoires in donors with group. A and B haplotypes suggest a ligand-instructed model of NK cell receptor acquisition. Blood 2011; 117: 98–107.

    Article  Google Scholar 

  13. Beziat V, Traherne JA, Liu LL, Jayaraman J, Enqvist M, Larsson S et al. Influence of KIR gene copy number on natural killer cell education. Blood 2013; 121: 4703–4707.

    Article  CAS  Google Scholar 

  14. Wright PW, Li H, Huehn A, O'Connor GM, Cooley S, Miller JS et al. Characterization of a weakly expressed KIR2DL1 variant reveals a novel upstream promoter that controls KIR expression. Genes Immun 2014; 15: 440–448.

    Article  CAS  Google Scholar 

  15. Li H, Pascal V, Martin MP, Carrington M, Anderson SK . Genetic control of variegated KIR gene expression: polymorphisms of the bi-directional KIR3DL1 promoter are associated with distinct frequencies of gene expression. PLoS Genet 2008; 4: e1000254.

    Article  Google Scholar 

  16. Charoudeh HN, Terszowski G, Czaja K, Gonzalez A, Schmitter K, Stern M . Modulation of the natural killer cell KIR repertoire by cytomegalovirus infection. Eur J Immunol 2013; 43: 480–487.

    Article  CAS  Google Scholar 

  17. Guinan KJ, Cunningham RT, Meenagh A, Gonzalez A, Dring MM, McGuinness BW et al. Signatures of natural selection and coevolution between killer cell immunoglobulin-like receptors (KIR) and HLA class I genes. Genes Immun 2010; 11: 467–478.

    Article  CAS  Google Scholar 

  18. Babor F, Manser AR, Fischer JC, Scherenschlich N, Enczmann J, Chazara O et al. KIR ligand C2 is associated with increased susceptibility to childhood ALL and confers an elevated risk for late relapse. Blood 2014; 124: 2248–2251.

    Article  CAS  Google Scholar 

  19. Guinan KJ, Cunningham RT, Meenagh A, Dring MM, Middleton D, Gardiner CM . Receptor systems controlling natural killer cell function are genetically stratified in Europe. Genes Immun 2010; 11: 67–78.

    Article  CAS  Google Scholar 

  20. Uhrberg M, Parham P, Wernet P, Definition of gene content for nine common group. B haplotypes of the Caucasoid population: KIR haplotypes contain between seven and eleven KIR genes. Immunogenetics 2002; 54: 221–229.

    Article  CAS  Google Scholar 

  21. Beziat V, Traherne J, Malmberg JA, Ivarsson MA, Bjorkstrom NK, Retiere C et al. Tracing dynamic expansion of human NK-cell subsets by high-resolution analysis of KIR repertoires and cellular differentiation. Eur J Immunol 2014; 44: 2192–2196.

    Article  CAS  Google Scholar 

  22. Pando MJ, Gardiner CM, Gleimer M, McQueen KL, Parham P . The protein made from a common allele of KIR3DL1 (3DL1*004) is poorly expressed at cell surfaces due to substitution at positions 86 in Ig domain 0 and 182 in Ig domain 1. J Immunol 2003; 171: 6640–6649.

    Article  CAS  Google Scholar 

  23. Lanier LL . NK cell recognition. Annu Rev Immunol 2005; 23: 225–274.

    Article  CAS  Google Scholar 

  24. Borrego F, Masilamani M, Marusina AI, Tang X, Coligan JE . The CD94/NKG2 family of receptors: from molecules and cells to clinical relevance. Immunol Res 2006; 35: 263–278.

    Article  CAS  Google Scholar 

  25. Pegram HJ, Andrews DM, Smyth MJ, Darcy PK, Kershaw MH . Activating and inhibitory receptors of natural killer cells. Immunol Cell Biol 2011; 89: 216–224.

    Article  Google Scholar 

  26. Middleton D, Curran M, Maxwell L . Natural killer cells and their receptors. Transpl Immunol 2002; 10: 147–164.

    Article  CAS  Google Scholar 

  27. Brown D, Trowsdale J, Allen R . The LILR family: modulators of innate and adaptive immune pathways in health and disease. Tissue Antigens 2004; 64: 215–225.

    Article  CAS  Google Scholar 

  28. Bari R, Bell T, Leung WH, Vong QP, Chan WK, Das Gupta N et al. Significant functional heterogeneity among KIR2DL1 alleles and a pivotal role of arginine 245. Blood 2009; 114: 5182–5190.

    Article  CAS  Google Scholar 

  29. Andersson S, Fauriat C, Malmberg JA, Ljunggren HG, Malmberg KJ . KIR acquisition probabilities are independent of self-HLA class I ligands and increase with cellular KIR expression. Blood 2009; 114: 95–104.

    Article  CAS  Google Scholar 

  30. Beziat V, Liu LL, Malmberg JA, Ivarsson MA, Sohlberg E, Bjorklund AT et al. NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs. Blood 2013; 121: 2678–2688.

    Article  CAS  Google Scholar 

  31. Davidson CL, Li NL, Burshtyn DN . LILRB1 polymorphism and surface phenotypes of natural killer cells. Hum Immunol 2010; 71: 942–949.

    Article  CAS  Google Scholar 

  32. Jiang W, Johnson C, Jayaraman J, Simecek N, Noble J, Moffatt MF et al. Copy number variation leads to considerable diversity for B but not A haplotypes of the human KIR genes encoding NK cell receptors. Genome Res 2012; 22: 1845–1854.

    Article  CAS  Google Scholar 

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Author notes

  1. K J Guinan

    Present address: Current address: BioAtlantis Ltd., Kerry Technology Park, Tralee, Co, Kerry, Ireland

Authors and Affiliations

  1. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Trinity College, Dublin 2, Ireland

    S E Dunphy, C Ní Chorcora & C M Gardiner

  2. Cambridge Institute for Medical Research, University of Cambridge,

    J Jayaraman & J A Traherne

  3. Division of Immunology, Cambridge, UK

    J Jayaraman & J A Traherne

  4. Department of Pathology, University of Cambridge, Cambridge, UK

    J A Traherne & J Trowsdale

  5. Immunology Laboratory, IRCCS AOU San Martino-IST, Largo Rosanna Benzi 10, Genova, Italy

    D Pende

  6. Transplant Immunology Laboratory, Royal Liverpool University Hospital, Liverpool, UK

    D Middleton

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  1. S E Dunphy
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Correspondence to C M Gardiner.

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Dunphy, S., Guinan, K., Chorcora, C. et al. 2DL1, 2DL2 and 2DL3 all contribute to KIR phenotype variability on human NK cells. Genes Immun 16, 301–310 (2015). https://doi.org/10.1038/gene.2015.15

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  • DOI: https://doi.org/10.1038/gene.2015.15

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