title: Coevolution of killer cell Ig-like receptors with HLA-C to become the major variable regulators of human NK cells.
abstract: Interactions between HLA class I and killer cell Ig-like receptors (KIRs) diversify human NK cell responses. Dominant KIR ligands are the C1 and C2 epitopes of MHC-C, a young locus restricted to humans and great apes. C1- and C1-specific KIRs evolved first, being present in orangutan and functionally like their human counterparts. Orangutans lack C2 and C2-specific KIRs, but have a unique C1+C2-specific KIR that binds equally to C1 and C2. A receptor with this specificity likely provided the mechanism by which C2-KIR interaction evolved from C1-KIR while avoiding a nonfunctional intermediate, that is, either orphan receptor or ligand. Orangutan inhibitory MHC-C-reactive KIRs pair with activating receptors of identical avidity and specificity, contrasting with the selective attenuation of human activating KIRs. The orangutan C1-specific KIR reacts or cross-reacts with all four polymorphic epitopes (C1, C2, Bw4, and A3/11) recognized by human KIRs, revealing their structural commonality. Saturation mutagenesis at specificity-determining position 44 demonstrates that KIRs are inherently restricted to binding just these four epitopes, either individually or in combination. This restriction frees most HLA-A and HLA-B variants to be dedicated TCR ligands, not subject to conflicting pressures from the NK cell and T cell arms of the immune response.
authors.affiliation: Immunology Program, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Anastazia M
authors.initials: AM
authors.lastname: Older Aguilar
authors.forename: Lisbeth A
authors.initials: LA
authors.lastname: Guethlein
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Adams
authors.forename: Laurent
authors.initials: L
authors.lastname: Abi-Rached
authors.forename: Achim K
authors.initials: AK
authors.lastname: Moesta
authors.forename: Peter
authors.initials: P
authors.lastname: Parham
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005075:Biological Evolution; D015236:HLA-C Antigens / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D057079:Pongo; D054340:Receptors, KIR / Q000235:genetics* / Q000276:immunology*
chemical_list: D015236:HLA-C Antigens; D054340:Receptors, KIR
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14326-31
references.pmid: 9826699
references.citation: Cell. 1978 May;14(1):9-20
references.pmid: 667938
references.citation: J Immunol. 1982 Jan;128(1):129-35
references.pmid: 6172474
references.citation: Methods Mol Biol. 2000;121:239-50
references.pmid: 10818730
references.citation: J Exp Med. 1995 Aug 1;182(2):605-9
references.pmid: 7629517
references.citation: Nat Genet. 2007 Jun;39(6):733-40
references.pmid: 17496894
references.citation: Annu Rev Immunol. 2002;20:217-51
references.pmid: 11861603
references.citation: Semin Immunol. 2008 Dec;20(6):343-52
references.pmid: 18635379
references.citation: Hum Immunol. 2005 Sep;66(9):989-97
references.pmid: 16360839
references.citation: J Immunol. 1997 May 1;158(9):4026-8
references.pmid: 9126959
references.citation: Nat Genet. 2002 Aug;31(4):429-34
references.pmid: 12134147
references.citation: Immunogenetics. 1982;15(2):151-66
references.pmid: 6174442
references.citation: Nat Immunol. 2001 May;2(5):452-60
references.pmid: 11323700
references.citation: Nature. 2000 Jun 1;405(6786):537-43
references.pmid: 10850706
references.citation: Mol Immunol. 2002 May;38(14):1007-21
references.pmid: 11955593
references.citation: J Immunol. 1995 Sep 1;155(5):2306-10
references.pmid: 7650366
references.citation: Immunogenetics. 2006 Jan;57(12):904-16
references.pmid: 16391939
references.citation: J Immunol. 1998 Jul 15;161(2):571-7
references.pmid: 9670929
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18692-7
references.pmid: 19837691
references.citation: Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4778-83
references.pmid: 10781084
references.citation: J Immunol. 2009 Mar 15;182(6):3618-27
references.pmid: 19265140
references.citation: PLoS Genet. 2009 Oct;5(10):e1000688
references.pmid: 19834558
references.citation: J Immunol. 2005 Oct 15;175(8):5222-9
references.pmid: 16210627
references.citation: Immunity. 2008 Nov 14;29(5):675-8
references.pmid: 19006692
references.citation: J Exp Med. 1996 Aug 1;184(2):735-40
references.pmid: 8760827
references.citation: Immunol Rev. 2006 Dec;214:56-72
references.pmid: 17100876
references.citation: J Exp Med. 2006 Mar 20;203(3):633-45
references.pmid: 16533882
references.citation: Mol Biol Evol. 2007 Jan;24(1):26-53
references.pmid: 17047029
references.citation: J Exp Med. 1995 Mar 1;181(3):1133-44
references.pmid: 7532677
references.citation: Immunity. 2000 Jun;12(6):687-98
references.pmid: 10894168
references.citation: Eur J Immunol. 2004 Jun;34(6):1673-9
references.pmid: 15162437
references.citation: Blood. 2008 Sep 15;112(6):2369-80
references.pmid: 18583565
references.citation: Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):7983-5
references.pmid: 1518825
references.citation: J Immunol. 2007 Jan 15;178(2):647-51
references.pmid: 17202323
references.citation: Annu Rev Immunol. 1996;14:619-48
references.pmid: 8717527
references.citation: Nat Rev Immunol. 2006 Aug;6(8):584-94
references.pmid: 16868549
references.citation: Science. 1995 Apr 21;268(5209):405-8
references.pmid: 7716543
references.citation: Blood. 2007 Jul 15;110(2):578-86
references.pmid: 17392508
references.citation: J Immunol. 2002 Jul 1;169(1):220-9
references.pmid: 12077248
references.citation: Genome Res. 2005 Jan;15(1):25-35
references.pmid: 15632087
references.citation: Immunity. 1995 May;2(5):439-49
references.pmid: 7749980
references.citation: Nature. 2002 Apr 18;416(6882):726-9
references.pmid: 11961552
references.citation: Semin Immunol. 2008 Dec;20(6):311-6
references.pmid: 19036608
references.citation: J Immunol. 2002 Jan 1;168(1):240-52
references.pmid: 11751968
references.citation: Clin Exp Immunol. 2007 Jul;149(1):1-8
references.pmid: 17521317
references.citation: Immunol Res. 2008;41(3):267-94
references.pmid: 18726714
references.citation: J Exp Med. 2009 Oct 26;206(11):2557-72
references.pmid: 19858347
references.citation: Immunol Today. 2000 Dec;21(12):611-4
references.pmid: 11114420
references.citation: J Immunol. 1989 May 1;142(9):3320-8
references.pmid: 2785140
references.citation: Mol Immunol. 2005 Feb;42(4):471-5
references.pmid: 15607801
references.citation: Immunity. 1997 Dec;7(6):753-63
references.pmid: 9430221
references.citation: J Exp Med. 1994 Oct 1;180(4):1235-42
references.pmid: 7931060
references.citation: Proc Natl Acad Sci U S A. 2010 Jun 1;107(22):10160-5
references.pmid: 20439706
references.citation: Eur J Immunol. 1997 Dec;27(12):3095-9
references.pmid: 9464792
references.citation: Curr Biol. 1998 Jul 30-Aug 13;8(16):R582-8
references.pmid: 9707399
references.citation: J Immunol. 1986 Dec 1;137(11):3671-4
references.pmid: 2431040
references.citation: Exp Hematol. 1996 Feb;24(3):406-15
references.pmid: 8599969
references.citation: Blood. 2009 Jul 2;114(1):95-104
references.pmid: 19304956
references.citation: Blood. 2003 May 1;101(9):3730-40
references.pmid: 12511415
references.citation: Transplantation. 2003 Jan 15;75(1):43-9
references.pmid: 12544869
references.citation: Immunol Rev. 2008 Aug;224:98-123
references.pmid: 18759923
references.citation: J Med Primatol. 2010 Aug;39(4):194-212
references.pmid: 20618586
references.citation: Immunity. 2006 Aug;25(2):331-42
references.pmid: 16901727
references.citation: J Exp Med. 1992 Mar 1;175(3):709-18
references.pmid: 1371301
references.citation: Immunol Today. 1996 May;17(5):212-4
references.pmid: 8991381
references.citation: Immunity. 2005 Mar;22(3):295-304
references.pmid: 15780987
references.citation: J Exp Med. 1999 Apr 5;189(7):1093-100
references.pmid: 10190900
references.citation: Immunol Res. 2006;35(3):263-78
references.pmid: 17172651
references.citation: J Mol Biol. 1988 Jun 20;201(4):751-4
references.pmid: 3172202
references.citation: Immunogenetics. 2009 Jan;61(1):27-41
references.pmid: 19009288
references.citation: J Immunol. 2008 Mar 15;180(6):3969-79
references.pmid: 18322206
references.citation: J Immunol. 2004 Jan 1;172(1):356-69
references.pmid: 14688344
references.citation: J Immunol. 1996 May 1;156(9):3098-101
references.pmid: 8617928
references.citation: J Immunol. 2007 Jul 1;179(1):491-504
references.pmid: 17579070
references.citation: Immunol Rev. 2001 Oct;183:41-64
references.pmid: 11782246
references.citation: Blood. 2010 Feb 11;115(6):1166-74
references.pmid: 19903900
references.citation: Science. 2005 Oct 14;310(5746):300-4
references.pmid: 16224019
references.citation: J Exp Med. 1996 Aug 1;184(2):505-18
references.pmid: 8760804
references.citation: Blood. 2001 Aug 1;98(3):705-13
references.pmid: 11468170
references.citation: Immunogenetics. 2007 Jun;59(6):517-22
references.pmid: 17450355
references.citation: J Immunol. 2009 Mar 15;182(6):3628-37
references.pmid: 19265141
references.citation: Cancer Biol Ther. 2009 Dec;8(23):2211-20
references.pmid: 19923897
references.citation: Immunogenetics. 1999 Sep;49(10):865-71
references.pmid: 10436180
references.citation: Biochemistry (Mosc). 2006;71 Suppl 1:S60-4, 4-5
references.pmid: 16487070
references.citation: Annu Rev Immunol. 1998;16:359-93
references.pmid: 9597134
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13224-9
references.pmid: 16141329
references.citation: Semin Immunol. 2008 Dec;20(6):317-20
references.pmid: 18656382