title: Tissue-resident exhausted effector memory CD8+ T cells accumulate in the retina during chronic experimental autoimmune uveoretinitis.
abstract: Experimental autoimmune uveoretinitis is a model for noninfectious posterior segment intraocular inflammation in humans. Although this disease is CD4(+) T cell dependent, in the persistent phase of disease CD8(+) T cells accumulate. We show that these are effector memory CD8(+) T cells that differ from their splenic counterparts with respect to surface expression of CD69, CD103, and Ly6C. These retinal effector memory CD8(+) T cells have limited cytotoxic effector function, are impaired in their ability to proliferate in response to Ag-specific stimulation, and upregulate programmed death 1 receptor. Treatment with fingolimod (FTY720) during the late phase of disease revealed that retinal CD8(+) T cells were tissue resident. Despite signs of exhaustion, these cells were functional, as their depletion resulted in an expansion of retinal CD4(+) T cells and CD11b(+) macrophages. These results demonstrate that, during chronic autoimmune inflammation, exhausted CD8(+) T cells become established in the local tissue. They are phenotypically distinct from peripheral CD8(+) T cells and provide local signals within the tissue by expression of inhibitory receptors such as programmed death 1 that limit persistent inflammation.
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, United Kingdom;
authors.forename: Joanne
authors.initials: J
authors.lastname: Boldison
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Chu
authors.forename: David A
authors.initials: DA
authors.lastname: Copland
authors.forename: Philippa J P
authors.initials: PJ
authors.lastname: Lait
authors.forename: Tarnjit K
authors.initials: TK
authors.lastname: Khera
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Dick
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Nicholson
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002645:Chickens; D002908:Chronic Disease; D004195:Disease Models, Animal; D006801:Humans; D007156:Immunologic Memory; D051379:Mice; D009928:Organ Specificity; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D012173:Retinitis / Q000276:immunology* / Q000473:pathology; D014603:Uveal Diseases / Q000276:immunology* / Q000473:pathology
chemical_list: C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor
references.citation: Nat Immunol. 2009 May;10(5):524-30
references.pmid: 19305395
references.citation: J Immunol. 2005 Aug 1;175(3):1851-7
references.pmid: 16034128
references.citation: Front Immunol. 2012 Nov 09;3:340
references.pmid: 23162555
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14733-8
references.pmid: 20679213
references.citation: Annu Rev Immunol. 2013;31:137-61
references.pmid: 23215646
references.citation: Cancer Res. 2008 Apr 15;68(8):2993-3000
references.pmid: 18413769
references.citation: Nature. 2004 Jan 22;427(6972):355-60
references.pmid: 14737169
references.citation: J Immunol. 2004 Aug 15;173(4):2849-54
references.pmid: 15295004
references.citation: Autoimmunity. 1993;16(2):83-93
references.pmid: 8180321
references.citation: Nature. 2006 Feb 9;439(7077):682-7
references.pmid: 16382236
references.citation: J Immunol. 2004 Apr 15;172(8):4875-82
references.pmid: 15067066
references.citation: Am J Pathol. 2012 Feb;180(2):672-81
references.pmid: 22119714
references.citation: Nat Immunol. 2011 Jun;12(6):492-9
references.pmid: 21739672
references.citation: J Exp Med. 2001 Sep 3;194(5):669-76
references.pmid: 11535634
references.citation: J Autoimmun. 2004 Aug;23(1):1-7
references.pmid: 15236747
references.citation: Nat Immunol. 2009 Jan;10(1):29-37
references.pmid: 19043418
references.citation: Blood. 2011 Apr 28;117(17):4501-10
references.pmid: 21385853
references.citation: Curr Eye Res. 1998 Apr;17(4):426-37
references.pmid: 9561835
references.citation: J Pharmacol Exp Ther. 2003 Apr;305(1):70-7
references.pmid: 12649354
references.citation: J Clin Invest. 2011 Oct;121(10):4170-9
references.pmid: 21946256
references.citation: Curr Opin Ophthalmol. 2007 Nov;18(6):481-6
references.pmid: 18163000
references.citation: Proc Natl Acad Sci U S A. 2010 May 18;107(20):9317-22
references.pmid: 20439719
references.citation: Invest Ophthalmol Vis Sci. 2009 Jun;50(6):2862-70
references.pmid: 19182257
references.citation: J Autoimmun. 2008 Dec;31(4):354-61
references.pmid: 18838247
references.citation: J Exp Med. 1996 Apr 1;183(4):1917-21
references.pmid: 8666949
references.citation: Acta Ophthalmol. 2011 Mar;89(2):e180-8
references.pmid: 20584001
references.citation: N Engl J Med. 2012 Jun 28;366(26):2443-54
references.pmid: 22658127
references.citation: Glia. 2011 May;59(5):841-56
references.pmid: 21360758
references.citation: Am J Pathol. 2012 Jan;180(1):235-45
references.pmid: 22067906
references.citation: J Exp Med. 2010 Mar 15;207(3):553-64
references.pmid: 20156972
references.citation: Immunology. 2003 Nov;110(3):386-96
references.pmid: 14632667
references.citation: Nat Immunol. 2007 Oct;8(10):1049-59
references.pmid: 17873878
references.citation: Immunology. 1993 Mar;78(3):393-8
references.pmid: 8097489
references.citation: Nature. 2006 Mar 23;440(7083):540-4
references.pmid: 16525420
references.citation: J Immunol Methods. 2003 Oct 1;281(1-2):65-78
references.pmid: 14580882
references.citation: Clin Immunol Immunopathol. 1985 Apr;35(1):103-10
references.pmid: 3158456
references.citation: Proc Natl Acad Sci U S A. 2010 Oct 19;107(42):17872-9
references.pmid: 20923878
references.citation: Immunity. 1998 Feb;8(2):177-87
references.pmid: 9491999
references.citation: J Leukoc Biol. 2002 Dec;72(6):1117-21
references.pmid: 12488492
references.citation: Springer Semin Immunopathol. 1999;21(2):113-24
references.pmid: 10457585
references.citation: Immunity. 2007 Oct;27(4):670-84
references.pmid: 17950003
references.citation: J Immunol. 2006 Feb 15;176(4):2079-83
references.pmid: 16455963
references.citation: J Virol. 2003 Apr;77(8):4911-27
references.pmid: 12663797
references.citation: Invest Ophthalmol Vis Sci. 2007 May;48(5):2178-84
references.pmid: 17460277
references.citation: Immunity. 2013 Jan 24;38(1):187-97
references.pmid: 23260195
references.citation: J Immunol. 2012 May 15;188(10):4866-75
references.pmid: 22504644
references.citation: Annu Rev Immunol. 2005;23:127-59
references.pmid: 15771568
references.citation: PLoS Pathog. 2012;8(11):e1003044
references.pmid: 23209415
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10691-6
references.pmid: 15249675
references.citation: J Virol. 2011 May;85(9):4085-94
references.pmid: 21345961
references.citation: Immunol Rev. 2010 Jul;236:219-42
references.pmid: 20636820
references.citation: Exp Eye Res. 2002 Jun;74(6):753-60
references.pmid: 12126948
references.citation: J Immunol. 2003 Feb 1;170(3):1283-90
references.pmid: 12538687
references.citation: Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16741-6
references.pmid: 21930933
references.citation: Nat Immunol. 2007 Mar;8(3):239-45
references.pmid: 17304234
references.citation: Invest Ophthalmol Vis Sci. 2007 Sep;48(9):4153-61
references.pmid: 17724201
references.citation: J Exp Med. 2010 Sep 27;207(10):2187-94
references.pmid: 20819927
references.citation: Immunology. 1993 Jun;79(2):255-62
references.pmid: 8102121
references.citation: Exp Eye Res. 2008 Oct;87(4):319-26
references.pmid: 18634784
references.citation: Annu Rev Immunol. 2004;22:745-63
references.pmid: 15032595
references.citation: Ocul Immunol Inflamm. 2009 Jan-Feb;17(1):47-55
references.pmid: 19294574
references.citation: Invest Ophthalmol Vis Sci. 2008 Dec;49(12):5458-65
references.pmid: 18757507
references.citation: Proc Natl Acad Sci U S A. 2012 May 1;109(18):7037-42
references.pmid: 22509047
references.citation: Invest Ophthalmol Vis Sci. 2000 Jan;41(1):127-31
references.pmid: 10634611
references.citation: Nat Med. 2010 May;16(5):586-91, 1p following 591
references.pmid: 20400961
references.citation: J Immunol. 2009 Aug 15;183(4):2321-9
references.pmid: 19635911
references.citation: Arch Ophthalmol. 2008 Oct;126(10):1390-5
references.pmid: 18852417