title: HLA reduces killer cell Ig-like receptor expression level and frequency in a humanized mouse model.
abstract: NK cells use NK cell receptors to be able to recognize and eliminate infected, transformed, and allogeneic cells. Human NK cells are prevented from killing autologous healthy cells by virtue of inhibitory NKRs, primarily killer cell Ig-like receptors (KIR) that bind "self" HLA class I molecules. Individual NK cells stably express a selected set of KIR, but it is currently disputed whether the fraction of NK cells expressing a particular inhibitory KIR is influenced by the presence of the corresponding HLA ligand. The extreme polymorphism of the KIR and HLA loci, with wide-ranging affinities for individual KIR and HLA allele combinations, has made this issue particularly hard to tackle. In this study, we used a transgenic mouse model to investigate the effect of HLA on KIR repertoire and function in the absence of genetic variation inside and outside the KIR locus. These H-2K(b-/-) and H-2D(b-/-) mice lacked ligands for inhibitory Ly49 receptors and were transgenic for HLA-Cw3 and a KIR B haplotype. In this reductionist system, the presence of HLA-Cw3 reduced the frequency of KIR2DL2(+) cells, as well as the surface expression levels of KIR2DL2. In addition, in the presence of HLA-Cw3, the frequency of NKG2A(+) cells and the surface expression levels of NKG2A were reduced. In line with these findings, both transgene-encoded KIR and endogenous NKG2A contributed to the rejection of cells lacking HLA-Cw3. These findings support the idea that HLA influences the human KIR repertoire.
authors: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. J.van_Bergen@lumc.nl
authors: Jeroen
authors: J
authors: van Bergen
authors: Allan
authors: A
authors: Thompson
authors: Melissa
authors: M
authors: van Pel
authors: Christelle
authors: C
authors: Retière
authors: Daniela
authors: D
authors: Salvatori
authors: David H
authors: DH
authors: Raulet
authors: John
authors: J
authors: Trowsdale
authors: Frits
authors: F
authors: Koning
mesh_terms: D000818:Animals; D006183:H-2 Antigens / Q000235:genetics; D015236:HLA-C Antigens / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018448:Models, Immunological; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D054340:Receptors, KIR / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D054343:Receptors, KIR2DL2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D015236:HLA-C Antigens; C038653:HLA-C*03 antigen; C515077:KIR2DL2 protein, human; C433932:KIR2DS2 protein, human; C527054:KLRC1 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D054340:Receptors, KIR; D054343:Receptors, KIR2DL2
references: Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4778-83
references: 10781084
references: Transplantation. 2005 May 15;79(9):1268-72
references: 15880083
references: Blood. 2008 Sep 15;112(6):2369-80
references: 18583565
references: Nature. 2005 Aug 4;436(7051):709-13
references: 16079848
references: Science. 2002 Mar 15;295(5562):2097-100
references: 11896281
references: Immunity. 2006 Aug;25(2):331-42
references: 16901727
references: J Exp Med. 1996 Apr 1;183(4):1817-27
references: 8666938
references: J Immunol. 2008 Mar 15;180(6):3969-79
references: 18322206
references: Eur J Immunol. 1999 Nov;29(11):3683-90
references: 10556824
references: J Immunol. 2009 Mar 1;182(5):2569-72
references: 19234149
references: Blood. 2005 Jun 1;105(11):4416-23
references: 15728129
references: Immunity. 1997 Dec;7(6):739-51
references: 9430220
references: Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):868-73
references: 11782535
references: Blood. 2011 Jan 6;117(1):98-107
references: 20935255
references: J Exp Med. 2005 Apr 4;201(7):1145-55
references: 15809355
references: J Immunol. 2003 Sep 15;171(6):3056-63
references: 12960331
references: J Immunol. 2002 Jul 1;169(1):239-47
references: 12077250
references: Eur J Immunol. 2004 Jun;34(6):1646-53
references: 15162434
references: J Immunol. 1999 Jun 15;162(12):6976-80
references: 10358137
references: Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14326-31
references: 9826699
references: Blood. 2007 Jul 1;110(1):433-40
references: 17371948
references: J Exp Med. 2006 Mar 20;203(3):633-45
references: 16533882
references: Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12879-84
references: 19561305
references: J Exp Med. 1999 Dec 20;190(12):1801-12
references: 10601355
references: Immunology. 2009 Oct;128(2):172-84
references: 19740374
references: Blood. 2009 Jul 2;114(1):95-104
references: 19304956
references: Proc Natl Acad Sci U S A. 1988 Aug;85(15):5664-8
references: 2840670
references: J Exp Med. 1998 Sep 7;188(5):973-8
references: 9730898
references: Nat Rev Immunol. 2010 Oct;10(10):724-34
references: 20818413