title: DEC-205-mediated antigen targeting to steady-state dendritic cells induces deletion of diabetogenic CD8⁺ T cells independently of PD-1 and PD-L1.
abstract: CD8⁺ T cells specific for islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) have been implicated in type 1 diabetes in both humans and non-obese diabetic (NOD) mice, in which T cells specific for IGRP₂₀₆₋₂₁₄ are highly prevalent. We sought to manipulate these pathogenic T cells by exploiting the ability of steady-state dendritic cells (DCs) to present antigens in a tolerogenic manner. The endocytic receptor DEC-205 was utilized to deliver an IGRP₂₀₆₋₂₁₄ mimotope to DCs in NOD mice, and the impact of this delivery on a polyclonal population of endogenous islet-reactive cognate T cells was determined. Assessment of islet-infiltrating CD8⁺ T cells showed a decrease in the percentage, and the absolute number, of endogenous IGRP₂₀₆₋₂₁₄-specific T cells when the mimotope was delivered to DCs, compared with delivery of a specificity control. Employing an adoptive transfer system, deletion of CD8⁺ T cells as a result of DEC-205-mediated antigen targeting was found to occur independently of programmed death-1 (PD-1) and its ligand (PD-L1), both often implicated in the regulation of peripheral T-cell tolerance. Given its promise for the manipulation of self-reactive polyclonal T cells demonstrated here, the distinctive characteristics of this antigen delivery system will be important to appreciate as its potential as an intervention for autoimmune diseases continues to be investigated.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Gayatri
authors.initials: G
authors.lastname: Mukherjee
authors.forename: Ari
authors.initials: A
authors.lastname: Geliebter
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Babad
authors.forename: Pere
authors.initials: P
authors.lastname: Santamaria
authors.forename: David V
authors.initials: DV
authors.lastname: Serreze
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Kristin V
authors.initials: KV
authors.lastname: Tarbell
authors.forename: Arlene
authors.initials: A
authors.lastname: Sharpe
authors.forename: Teresa P
authors.initials: TP
authors.lastname: DiLorenzo
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D000937:Antigen-Antibody Reactions; D000941:Antigens / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology*; D060890:B7-H1 Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology*; D018655:Lymphocyte Count; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology*
chemical_list: D000906:Antibodies; D000941:Antigens; D015703:Antigens, CD; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; C093569:DEC-205 receptor; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011956:Receptors, Cell Surface
keywords: Autoimmunity; NOD mice; diabetes
references.citation: Nat Immunol. 2005 Dec;6(12):1219-27
references.pmid: 16244650
references.citation: Cell Immunol. 1995 Jun;163(1):148-56
references.pmid: 7758125
references.citation: Diabetes. 2007 Mar;56(3):613-21
references.pmid: 17327428
references.citation: J Exp Med. 2004 Mar 15;199(6):815-24
references.pmid: 15024047
references.citation: J Immunol. 1995 Mar 1;154(5):2494-503
references.pmid: 7868915
references.citation: J Exp Med. 1997 Nov 17;186(10):1663-76
references.pmid: 9362527
references.citation: Nat Immunol. 2005 Mar;6(3):280-6
references.pmid: 15685176
references.citation: J Autoimmun. 2010 Dec;35(4):390-7
references.pmid: 20850948
references.citation: J Exp Med. 2002 Dec 16;196(12):1627-38
references.pmid: 12486105
references.citation: J Cell Biol. 2000 Oct 30;151(3):673-84
references.pmid: 11062267
references.citation: J Clin Invest. 2006 Dec;116(12):3258-65
references.pmid: 17143333
references.citation: J Immunol. 2010 Apr 15;184(8):4196-204
references.pmid: 20220085
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8384-8
references.pmid: 12815107
references.citation: Nature. 2006 Feb 9;439(7077):682-7
references.pmid: 16382236
references.citation: Blood. 2003 Jun 15;101(12):4862-9
references.pmid: 12543858
references.citation: Eur J Immunol. 2003 Oct;33(10):2706-16
references.pmid: 14515254
references.citation: Mol Immunol. 2010 May;47(9):1765-73
references.pmid: 20347150
references.citation: Science. 2007 Jan 5;315(5808):107-11
references.pmid: 17204652
references.citation: J Immunol. 2002 Nov 15;169(10):5538-45
references.pmid: 12421930
references.citation: J Immunol. 2003 Jul 1;171(1):47-60
references.pmid: 12816982
references.citation: J Immunol. 2001 Jul 15;167(2):655-66
references.pmid: 11441068
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):13682-7
references.pmid: 21825122
references.citation: J Exp Med. 2006 Apr 17;203(4):883-95
references.pmid: 16606670
references.citation: J Immunol Methods. 2008 Nov 30;339(1):66-73
references.pmid: 18782577
references.citation: J Immunol. 2008 Nov 15;181(10):6923-33
references.pmid: 18981112
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6374-9
references.pmid: 18430797
references.citation: Diabetes. 2011 Apr;60(4):1229-36
references.pmid: 21346176
references.citation: Immunity. 2010 Apr 23;32(4):488-99
references.pmid: 20412759
references.citation: Blood. 2010 Nov 11;116(19):3828-38
references.pmid: 20668230
references.citation: Immunity. 2004 Jun;20(6):695-705
references.pmid: 15189735
references.citation: Diabetes. 1989 Nov;38(11):1446-55
references.pmid: 2576007
references.citation: Immunity. 2007 Jul;27(1):111-22
references.pmid: 17629517
references.citation: J Immunol. 2007 Oct 15;179(8):5064-70
references.pmid: 17911591
references.citation: J Clin Invest. 2003 Jan;111(2):217-23
references.pmid: 12531877
references.citation: J Exp Med. 2003 Jul 7;198(1):63-9
references.pmid: 12847137
references.citation: Clin Immunol. 2002 Dec;105(3):332-41
references.pmid: 12498815
references.citation: J Immunol. 2004 Dec 1;173(11):6727-34
references.pmid: 15557165
references.citation: Immunity. 2010 Apr 23;32(4):568-80
references.pmid: 20381385
references.citation: Immunol Rev. 2010 Jul;236:219-42
references.pmid: 20636820
references.citation: Nat Med. 2005 Jun;11(6):645-52
references.pmid: 15908957
references.citation: Nature. 2000 Aug 17;406(6797):739-42
references.pmid: 10963600
references.citation: Mol Immunol. 2008 Aug;45(13):3567-72
references.pmid: 18585785
references.citation: Nature. 1995 May 11;375(6527):151-5
references.pmid: 7753172
references.citation: J Immunol. 2000 Mar 15;164(6):2978-86
references.pmid: 10706685
references.citation: J Immunol. 2011 Aug 1;187(3):1097-105
references.pmid: 21697456
references.citation: Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17280-5
references.pmid: 20855626
references.citation: J Exp Med. 2001 Sep 17;194(6):769-79
references.pmid: 11560993
references.citation: J Immunol. 2000 Apr 1;164(7):3913-8
references.pmid: 10725754
references.citation: J Immunol. 2004 Aug 15;173(4):2530-41
references.pmid: 15294969
references.citation: J Immunol. 2001 Jul 15;167(2):741-8
references.pmid: 11441078