Abstract
Certain combinations of the killer immunoglobulin-like receptors (KIR) and major histocompatibility complex class I ligands in humans predispose carriers to a variety of diseases, requiring sophisticated genotyping of the highly polymorphic and diverse KIR and HLA genes. Particularly, KIR genotyping is challenging due to polymorphisms (allelic substitutions), genomic diversity (presence/absence of genes), and frequent duplications. Rhesus macaques are often used as important animal models of human diseases such as, e.g. AIDS. However, typing of rhesus macaque KIR genes has not been described so far. In this study, we report the identification of additional novel rhesus macaque KIR cDNA sequences and a sequence-specific KIR genotyping assay. From a cohort of four rhesus macaque families with a total of 70 individuals, we identified 25 distinct KIR genotypes. Segregation analyses of KIR genes and of two polymorphic microsatellite markers allowed the identification of 21 distinct KIR haplotypes in these families, with five to 11 segregating KIR genes per haplotype. Our analyses confirmed and extended knowledge on differential gene KIR gene content in macaques and indicate that rhesus macaque and human KIR haplotypes show a comparable level of diversity and complexity.
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Abi-Rached L, Kuhl H, Roos C, ten Hallers B, Zhu B, Carbone L, de Jong PJ, Mootnick AR, Knaust F, Reinhardt R, Parham P, Walter L (2010) A small, variable and irregular killer cell immunoglobulin-like receptor (KIR) locus accompanies the absence of MHC-C and MHC-G in gibbons. J Immunol (in press)
Bimber BN, Moreland AJ, Wiseman RW, Hughes AL, O'Connor DH (2008) Complete characterization of killer Ig-like receptor (KIR) haplotypes in Mauritian cynomolgus macaques: novel insights into nonhuman primate KIR gene content and organization. J Immunol 181:6301–6308
Blokhuis JH, Doxiadis GG, Bontrop RE (2009a) A splice site mutation converts an inhibitory killer cell Ig-like receptor into an activating one. Mol Immunol 46:640–648
Blokhuis JH, van der Wiel MK, Doxiadis GG, Bontrop RE (2009b) Evidence for balancing selection acting on KIR2DL4 genotypes in rhesus macaques of Indian origin. Immunogenetics 61:503–512
Blokhuis JH, van der Wiel MK, Doxiadis GGM, Bontrop RE (2010) The mosaic of KIR haplotypes in rhesus macaques. Immunogenetics. doi:10.1007/s00251-010-0434-3
Bontrop RE, Watkins DI (2005) MHC polymorphism: AIDS susceptibility in non-human primates. Trends Immunol 26:227–233
Feng J, Garrity D, Call ME, Moffett H, Wucherpfennig KW (2005) Convergence on a distinctive assembly mechanism by unrelated families of activating immune receptors. Immunity 22:427–438
Gardiner CM (2008) Killer cell immunoglobulin-like receptors on NK cells: the how, where and why. Int J Immunogenet 35:1–8
Hershberger KL, Shyam R, Miura A, Letvin NL (2001) Diversity of the killer cell Ig-like receptors of rhesus monkeys. J Immunol 166:4380–4390
Hiby SE, Regan L, Lo W, Farrell L, Carrington M, Moffett A (2008) Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage. Hum Reprod 23:972–976
Houtchens KA, Nichols RJ, Ladner MB, Boal HE, Sollars C, Geraghty DE, Davis LM, Parham P, Trachtenberg EA (2007) High-throughput killer cell immunoglobulin-like receptor genotyping by MALDI-TOF mass spectrometry with discovery of novel alleles. Immunogenetics 59:525–537
Hsu KC, Chida S, Geraghty DE, Dupont B (2002) The killer cell immunoglobulin-like receptor (KIR) genomic region: gene-order, haplotypes and allelic polymorphism. Immunol Rev 190:40–52
Johansson S, Hall H, Berg L, Hoglund P (2006) NK cells in autoimmune disease. Curr Top Microbiol Immunol 298:259–277
Kelley J, Walter L, Trowsdale J (2005) Comparative genomics of natural killer cell receptor gene clusters. PLoS Genet 1:129–139
Khakoo SI, Thio CL, Martin MP, Brooks CR, Gao X, Astemborski J, Cheng J, Goedert JJ, Vlahov D, Hilgartner M, Cox S, Little AM, Alexander GJ, Cramp ME, O'Brien SJ, Rosenberg WM, Thomas DL, Carrington M (2004) HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 305:872–874
Lanier LL (1998) NK cell receptors. Annu Rev Immunol 16:359–393
Lanier LL (2008) Evolutionary struggles between NK cells and viruses. Nat Rev Immunol 8:259–268
Long EO (1999) Regulation of immune responses through inhibitory receptors. Annu Rev Immunol 17:875–904
Marsh SG, Parham P, Dupont B, Geraghty DE, Trowsdale J, Middleton D, Vilches C, Carrington M, Witt C, Guethlein LA, Shilling H, Garcia CA, Hsu KC, Wain H (2003) Killer-cell immunoglobulin-like receptor (KIR) nomenclature report, 2002. Immunogenetics 55:220–226
Martin MP, Bashirova A, Traherne J, Trowsdale J, Carrington M (2003) Cutting edge: expansion of the KIR locus by unequal crossing over. J Immunol 171:2192–2195
Martin M, Qi Y, Gao X, Yamada E, Martin J, Pereyra F, Colombo S, Brown E, Shupert W, Phair J, Goedert J, Buchbinder S, Kirk G, Telenti A, Connors M, O'brien S, Walker B, Parham P, Deeks S, McVicar D, Carrington M (2007) Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1. Nat Genet 39:733–740
Martin MP, Single RM, Wilson MJ, Trowsdale J, Carrington M (2008) KIR haplotypes defined by segregation analysis in 59 Centre d'Etude Polymorphisme Humain (CEPH) families. Immunogenetics 60:767–774
Nelson G, Martin M, Gladman D, Wade J, Trowsdale J, Carrington M (2004) Cutting edge: heterozygote advantage in autoimmune disease: hierarchy of protection/susceptibility conferred by HLA and killer Ig-like receptor combinations in psoriatic arthritis. J Immunol 173:4273–4276
Norman PJ, Abi-Rached L, Gendzekhadze K, Hammond JA, Moesta AK, Sharma D, Graef T, McQueen KL, Guethlein LA, Carrington CV, Chandanayingyong D, Chang YH, Crespi C, Saruhan-Direskeneli G, Hameed K, Kamkamidze G, Koram KA, Layrisse Z, Matamoros N, Mila J, Park MH, Pitchappan RM, Ramdath DD, Shiau MY, Stephens HA, Struik S, Tyan D, Verity DH, Vaughan RW, Davis RW, Fraser PA, Riley EM, Ronaghi M, Parham P (2009) Meiotic recombination generates rich diversity in NK cell receptor genes, alleles, and haplotypes. Genome Res 19:757–769
Otting N, de Vos-Rouweler AJ, Heijmans CM, de Groot NG, Doxiadis GG, Bontrop RE (2007) MHC class I A region diversity and polymorphism in macaque species. Immunogenetics 59:367–375
Otting N, Heijmans CM, van der Wiel M, de Groot NG, Doxiadis GG, Bontrop RE (2008) A snapshot of the Mamu-B genes and their allelic repertoire in rhesus macaques of Chinese origin. Immunogenetics 60:507–514
Parham P (2005) MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol 5:201–214
Rajalingam R, Parham P, Abi-Rached L (2004) Domain shuffling has been the main mechanism forming new hominoid killer cell Ig-like receptors. J Immunol 172:356–369
Robinson J, Marsh SG (2007) IPD: the Immuno Polymorphism Database. Methods Mol Biol 409:61–74
Sambrook JG, Bashirova A, Palmer S, Sims S, Trowsdale J, Abi-Rached L, Parham P, Carrington M, Beck S (2005) Single haplotype analysis demonstrates rapid evolution of the killer immunoglobulin-like receptor (KIR) loci in primates. Genome Res 15:25–35
Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG (1997) The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res 25:4876–4882
Uhrberg M (2005) The KIR gene family: life in the fast lane of evolution. Eur J Immunol 35:10–15
Uhrberg M, Valiante NM, Shum BP, Shilling HG, Lienert-Weidenbach K, Corliss B, Tyan D, Lanier LL, Parham P (1997) Human diversity in killer cell inhibitory receptor genes. Immunity 7:753–763
Valiante NM, Uhrberg M, Shilling HG, Lienert-Weidenbach K, Arnett KL, D'Andrea A, Phillips JH, Lanier LL, Parham P (1997) Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors. Immunity 7:739–751
Vilches C, Parham P (2002) KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu Rev Immunol 20:217–251
Vilches C, Castaño J, Gómez-Lozano N, Estefanía E (2007) Facilitation of KIR genotyping by a PCR-SSP method that amplifies short DNA fragments. Tissue Antigens 70:415–422
Wilson MJ, Torkar M, Haude A, Milne S, Jones T, Sheer D, Beck S, Trowsdale J (2000) Plasticity in the organization and sequences of human KIR/ILT gene families. Proc Natl Acad Sci USA 97:4778–4783
Acknowledgement
The authors gratefully acknowledge the expert technical assistance of Nicole Otto. PK is a member of the Göttingen Graduate School of Neurosciences and Molecular Biology (GGNB) "Molecular Biology of Microbial, Animal and Plant Cells". This study was supported by European Union grant "EUPRIM-Net" (FP6 026155) to LW.
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Kruse, P.H., Rosner, C. & Walter, L. Characterization of rhesus macaque KIR genotypes and haplotypes. Immunogenetics 62, 281–293 (2010). https://doi.org/10.1007/s00251-010-0433-4
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DOI: https://doi.org/10.1007/s00251-010-0433-4