title: Amelioration of arthritis through mobilization of peptide-specific CD8+ regulatory T cells.
abstract: Current therapies to treat autoimmune disease focus mainly on downstream targets of autoimmune responses, including effector cells and cytokines. A potentially more effective approach would entail targeting autoreactive T cells that initiate the disease cascade and break self tolerance. The murine MHC class Ib molecule Qa-1b (HLA-E in humans) exhibits limited polymorphisms and binds to 2 dominant self peptides: Hsp60(p216) and Qdm. We found that peptide-induced expansion of tetramer-binding CD8(+) Tregs that recognize Qa-1-Hsp60(p216) but not Qa-1-Qdm strongly inhibited collagen-induced arthritis, an animal model of human rheumatoid arthritis. Perforin-dependent elimination of autoreactive follicular Th (T(FH)) and Th17 cells by CD8(+) Tregs inhibited disease development. Infusion of in vitro-expanded CD8(+) Tregs increased the efficacy of methotrexate treatment and halted disease progression after clinical onset, suggesting an alternative approach to this first-line treatment. Moreover, infusion of small numbers of Qa-1-Hsp60(p216)-specific CD8(+) Tregs resulted in robust inhibition of autoimmune arthritis, confirming the inhibitory effects of Hsp60(p216) peptide immunization. These results suggest that strategies designed to expand Qa-1-restricted (HLA-E-restricted), peptide-specific CD8(+) Tregs represent a promising therapeutic approach to autoimmune disorders.
authors: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors: Jianmei W
authors: JW
authors: Leavenworth
authors: Xiaolei
authors: X
authors: Tang
authors: Hye-Jung
authors: HJ
authors: Kim
authors: Xiaoyang
authors: X
authors: Wang
authors: Harvey
authors: H
authors: Cantor
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000517:prevention & control*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000502:physiology / Q000637:transplantation; D002478:Cells, Cultured; D018834:Chaperonin 60 / Q000235:genetics / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007114:Immunization; D019409:Interleukin-15 / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000235:genetics / Q000276:immunology; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000276:immunology*; D010455:Peptides / Q000276:immunology; D054353:Perforin / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000502:physiology / Q000637:transplantation; D058504:Th17 Cells / Q000276:immunology
chemical_list: D018834:Chaperonin 60; D015395:Histocompatibility Antigens Class I; C557066:Hspd1 protein, mouse; D019409:Interleukin-15; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; D010455:Peptides; C032907:Q surface antigens; C090580:Qdm protein, mouse; D054353:Perforin; D008727:Methotrexate
references: Nat Genet. 2011 Jul 10;43(8):761-7
references: 21743469
references: J Immunol. 2003 May 15;170(10):5027-33
references: 12734347
references: Pharmacol Rev. 2005 Jun;57(2):163-72
references: 15914465
references: Nature. 2010 Sep 16;467(7313):328-32
references: 20844537
references: Nat Immunol. 2004 May;5(5):516-23
references: 15098030
references: Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2010-5
references: 21233417
references: Arthritis Res Ther. 2005;7(2):R402-15
references: 15743488
references: Nat Immunol. 2012 Apr 22;13(6):579-86
references: 22522492
references: Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2562-7
references: 20133787
references: Arthritis Rheum. 2003 May;48(5):1452-60
references: 12746920
references: J Exp Med. 2002 Dec 2;196(11):1403-14
references: 12461076
references: Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):14584-9
references: 21873193
references: Immunol Rev. 2010 Jan;233(1):97-111
references: 20192995
references: J Immunol. 2006 Nov 1;177(9):6072-80
references: 17056533
references: Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9166-71
references: 16757567
references: J Immunol. 2005 Oct 1;175(7):4255-64
references: 16177065
references: Nat Rev Immunol. 2005 Nov;5(11):853-65
references: 16261173
references: Eur J Immunol. 2001 Jan;31(1):87-93
references: 11169442
references: Clin Vaccine Immunol. 2006 Feb;13(2):289-96
references: 16467340
references: Science. 1996 Oct 4;274(5284):94-6
references: 8810254
references: N Engl J Med. 2011 Dec 1;365(22):2129-31
references: 22129258
references: Immunity. 2007 May;26(5):593-604
references: 17509909
references: Nat Rev Rheumatol. 2010 Mar;6(3):175-8
references: 20197777
references: N Engl J Med. 2011 Dec 1;365(22):2067-77
references: 22129253
references: Nat Protoc. 2009;4(4):565-81
references: 19373228
references: Nat Med. 2011 Jul 24;17(8):983-8
references: 21785430
references: Annu Rev Immunol. 2011;29:621-63
references: 21314428
references: J Neuroimmunol. 2010 Jun;223(1-2):65-72
references: 20430449
references: Arthritis Res Ther. 2007;9(6):223
references: 18177509
references: J Immunol. 2009 Dec 15;183(12):8268-79
references: 20007590
references: Nat Genet. 2010 Nov;42(11):985-90
references: 20953190
references: Autoimmun Rev. 2007 Nov;7(1):65-70
references: 17967728
references: Eur J Immunol. 2009 Aug;39(8):2040-4
references: 19672892
references: Lancet. 2005 Jul 2-8;366(9479):50-6
references: 15993233
references: Semin Immunol. 2011 Dec;23(6):446-52
references: 22136694
references: Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):534-9
references: 19118203
references: Exp Neurol. 2010 Apr;222(2):235-42
references: 20070942
references: N Engl J Med. 2011 Dec 1;365(22):2055-66
references: 22129252
references: J Immunol. 1998 Jun 1;160(11):5654-60
references: 9605172
references: Arthritis Rheum. 2010 Aug;62(8):2192-205
references: 20506322
references: Arthritis Res Ther. 2005;7(2):R291-301
references: 15743476
references: Nat Med. 2011 Jul 24;17(8):975-82
references: 21785433
references: Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19420-5
references: 19047627
references: Semin Immunol. 2007 Dec;19(6):362-71
references: 18035554
references: J Cell Physiol. 2008 Sep;216(3):742-9
references: 18393273