title: Ly9 (CD229) Cell-Surface Receptor is Crucial for the Development of Spontaneous Autoantibody Production to Nuclear Antigens.
abstract: The Signaling Lymphocyte Activation Molecule Family (SLAMF) genes, which encode cell-surface receptors that modulate innate and adaptive immune responses, lay within a genomic region of human and mouse chromosome 1 that confers a predisposition for the development of systemic lupus erythematosus (SLE). Herein, we demonstrate that the SLAMF member Ly9 arises as a novel receptor contributing to the reinforcement of tolerance. Specifically, Ly9-deficient mice spontaneously developed features of systemic autoimmunity such as the production of anti-nuclear antibodies (ANA), -dsDNA, and -nucleosome autoantibodies, independently of genetic background [(B6.129) or (BALB/c.129)]. In aged (10- to 12-month-old) Ly9 (-/-) mice key cell subsets implicated in autoimmunity were expanded, e.g., T follicular helper (Tfh) as well as germinal center (GC) B cells. More importantly, in vitro functional experiments showed that Ly9 acts as an inhibitory receptor of IFN-γ producing CD4(+) T cells. Taken together, our findings reveal that the Ly9 receptor triggers cell intrinsic safeguarding mechanisms to prevent a breach of tolerance, emerging as a new non-redundant inhibitory cell-surface receptor capable of disabling autoantibody responses.
authors.affiliation: Immunology Unit, Department of Cell Biology, Immunology and Neurosciences, Medical School, University of Barcelona , Barcelona , Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: de Salort
authors.forename: Marta
authors.initials: M
authors.lastname: Cuenca
authors.forename: Cox
authors.initials: C
authors.lastname: Terhorst
authors.forename: Pablo
authors.initials: P
authors.lastname: Engel
authors.forename: Xavier
authors.initials: X
authors.lastname: Romero
keywords: Ly9 (CD229; SLAMF; SLAMF3); anti-DNA autoantibodies; disease susceptibility; murine Lupus; systemic lupus erythematosus
references.citation: Nat Rev Rheumatol. 2010 Dec;6(12):683-92
references.pmid: 21060334
references.citation: Trends Immunol. 2009 Sep;30(9):455-64
references.pmid: 19699150
references.citation: Trends Immunol. 2013 Feb;34(2):50-8
references.pmid: 23017731
references.citation: Clin Exp Immunol. 2012 Jan;167(1):7-14
references.pmid: 22132879
references.citation: Nat Rev Immunol. 2006 Jan;6(1):56-66
references.pmid: 16493427
references.citation: Springer Semin Immunopathol. 2006 Oct;28(2):175-84
references.pmid: 16953439
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6670-5
references.pmid: 10841565
references.citation: Immunity. 2010 Feb 26;32(2):253-65
references.pmid: 20153220
references.citation: J Immunol. 2004 Apr 1;172(7):4159-66
references.pmid: 15034028
references.citation: J Immunol. 2004 Jul 1;173(1):68-78
references.pmid: 15210760
references.citation: J Biol Chem. 2012 Nov 2;287(45):38168-77
references.pmid: 22989874
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14869-74
references.pmid: 9843982
references.citation: N Engl J Med. 2011 Dec 1;365(22):2110-21
references.pmid: 22129255
references.citation: Science. 2006 Jun 16;312(5780):1665-9
references.pmid: 16778059
references.citation: Curr Opin Immunol. 2010 Dec;22(6):706-14
references.pmid: 21094032
references.citation: J Immunol. 2006 Jan 1;176(1):291-300
references.pmid: 16365421
references.citation: J Exp Med. 2004 Jul 19;200(2):261-6
references.pmid: 15263031
references.citation: Nat Immunol. 2009 Mar;10(3):297-305
references.pmid: 19151721
references.citation: Annu Rev Immunol. 2011;29:665-705
references.pmid: 21219180
references.citation: Int Immunol. 2011 Feb;23(2):149-58
references.pmid: 21278219
references.citation: Tissue Antigens. 2007 Nov;70(5):355-62
references.pmid: 17919264
references.citation: Immunol Rev. 2012 May;247(1):143-59
references.pmid: 22500838
references.citation: Semin Immunol. 2011 Apr;23(2):67-83
references.pmid: 21288738
references.citation: Nat Rev Immunol. 2003 Oct;3(10):813-21
references.pmid: 14523387
references.citation: Immunity. 2004 Dec;21(6):769-80
references.pmid: 15589166
references.citation: Blood. 2001 Jun 15;97(12):3867-74
references.pmid: 11389028
references.citation: Nat Rev Rheumatol. 2010 Jun;6(6):339-47
references.pmid: 20440285
references.citation: J Immunol. 2007 Feb 15;178(4):2352-60
references.pmid: 17277141
references.citation: Arthritis Res. 2001;3(3):136-41
references.pmid: 11299053
references.citation: J Immunol. 2011 Jul 1;187(1):21-5
references.pmid: 21622868
references.citation: Semin Immunopathol. 2010 Jun;32(2):157-71
references.pmid: 20146065
references.citation: Curr Opin Immunol. 2006 Dec;18(6):656-64
references.pmid: 17011767
references.citation: J Immunol. 2013 Jan 1;190(1):21-6
references.pmid: 23225888
references.citation: Adv Immunol. 2008;97:177-250
references.pmid: 18501771
references.citation: Nat Med. 2012 Jun 06;18(6):871-82
references.pmid: 22674006
references.citation: Methods Mol Biol. 2004;271:25-35
references.pmid: 15146110
references.citation: J Immunol. 2005 May 15;174(10):5977-86
references.pmid: 15879090
references.citation: N Engl J Med. 2008 Feb 28;358(9):929-39
references.pmid: 18305268
references.citation: BMC Immunol. 2011 Jan 20;12:7
references.pmid: 21251257
references.citation: J Exp Med. 2012 Jul 2;209(7):1241-53
references.pmid: 22753927
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1787-92
references.pmid: 11172029
references.citation: Curr Opin Rheumatol. 2006 Sep;18(5):451-5
references.pmid: 16896281
references.citation: J Clin Invest. 1997 Feb 15;99(4):725-31
references.pmid: 9045876
references.citation: J Clin Invest. 1999 Jun;103(12):1685-95
references.pmid: 10377175
references.citation: J Immunol. 2001 Aug 15;167(4):1886-90
references.pmid: 11489967
references.citation: J Immunol. 2005 Jun 1;174(11):7033-42
references.pmid: 15905546
references.citation: Nature. 2008 Oct 9;455(7214):764-9
references.pmid: 18843362
references.citation: Science. 1987 May 22;236(4804):944-7
references.pmid: 3107127
references.citation: J Exp Med. 2009 Mar 16;206(3):561-76
references.pmid: 19221396
references.citation: Immunity. 2012 Nov 16;37(5):880-92
references.pmid: 23159227
references.citation: J Exp Med. 1999 Dec 6;190(11):1697-710
references.pmid: 10587360
references.citation: J Immunol. 2012 Feb 1;188(3):1206-12
references.pmid: 22184727
references.citation: Dev Immunol. 2002 Mar;9(1):35-45
references.pmid: 12353661
references.citation: Arthritis Res Ther. 2011;13(5):243
references.pmid: 22078750
references.citation: J Exp Med. 2011 Apr 11;208(4):811-22
references.pmid: 21422172
references.citation: J Immunol. 2005 Oct 1;175(7):4309-19
references.pmid: 16177071
references.citation: J Clin Invest. 2003 Oct;112(8):1211-22
references.pmid: 14561706
references.citation: J Immunol. 2003 Mar 1;170(5):2293-301
references.pmid: 12594250