title: T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice.
abstract: Many autoimmune diseases exhibit familial aggregation, indicating that they have genetic determinants. Single nucleotide polymorphisms in PTPN2, which encodes T cell protein tyrosine phosphatase (TCPTP), have been linked with the development of several autoimmune diseases, including type 1 diabetes and Crohn's disease. In this study, we have identified TCPTP as a key negative regulator of TCR signaling, which might explain the association of PTPN2 SNPs with autoimmune disease. We found that TCPTP dephosphorylates and inactivates Src family kinases to regulate T cell responses. Using T cell-specific TCPTP-deficient mice, we established that TCPTP attenuates T cell activation and proliferation in vitro and blunts antigen-induced responses in vivo. TCPTP deficiency lowered the in vivo threshold for TCR-dependent CD8(+) T cell proliferation. Consistent with this, T cell-specific TCPTP-deficient mice developed widespread inflammation and autoimmunity that was transferable to wild-type recipient mice by CD8(+) T cells alone. This autoimmunity was associated with increased serum levels of proinflammatory cytokines and anti-nuclear antibodies, T cell infiltrates in non-lymphoid tissues, and liver disease. These data indicate that TCPTP is a critical negative regulator of TCR signaling that sets the threshold for TCR-induced naive T cell responses to prevent autoimmune and inflammatory disorders arising.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Florian
authors.initials: F
authors.lastname: Wiede
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Shields
authors.forename: Sock Hui
authors.initials: SH
authors.lastname: Chew
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kyparissoudis
authors.forename: Catherine
authors.initials: C
authors.lastname: van Vliet
authors.forename: Sandra
authors.initials: S
authors.lastname: Galic
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Russell
authors.forename: Dale I
authors.initials: DI
authors.lastname: Godfrey
authors.forename: Tony
authors.initials: T
authors.lastname: Tiganis
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000201:enzymology / Q000209:etiology* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D007108:Immune Tolerance / Q000276:immunology*; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011828:Radiation Chimera; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000201:enzymology* / Q000276:immunology; D060168:Thymocytes / Q000473:pathology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000974:Antibodies, Antinuclear; D011948:Receptors, Antigen, T-Cell; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; D019061:src-Family Kinases; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; C516653:Ptpn2 protein, mouse
references.citation: J Immunol. 2001 Jan 15;166(2):1308-13
references.pmid: 11145714
references.citation: Immunity. 2008 Dec 19;29(6):848-62
references.pmid: 19100699
references.citation: J Exp Med. 2008 Jan 21;205(1):245-56
references.pmid: 18195075
references.citation: Proc Natl Acad Sci U S A. 2004 Oct 12;101(41):14859-64
references.pmid: 15465914
references.citation: Nature. 2007 Jun 7;447(7145):661-78
references.pmid: 17554300
references.citation: J Immunol. 2007 Oct 1;179(7):4635-44
references.pmid: 17878361
references.citation: Science. 1994 Jul 1;265(5168):103-6
references.pmid: 8016642
references.citation: Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1680-5
references.pmid: 9050838
references.citation: Science. 1996 May 24;272(5265):1173-6
references.pmid: 8638162
references.citation: Curr Biol. 2002 Mar 19;12(6):446-53
references.pmid: 11909529
references.citation: Nat Rev Immunol. 2009 Mar;9(3):207-13
references.pmid: 19151748
references.citation: Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12070-4
references.pmid: 8618846
references.citation: Biochem J. 2007 Feb 15;402(1):1-15
references.pmid: 17238862
references.citation: Immunity. 1995 Sep;3(3):273-82
references.pmid: 7552993
references.citation: Eur J Immunol. 1999 Dec;29(12):3845-54
references.pmid: 10601992
references.citation: Trends Immunol. 2009 Sep;30(9):430-8
references.pmid: 19699149
references.citation: Immunol Cell Biol. 1998 Feb;76(1):34-40
references.pmid: 9553774
references.citation: Nat Immunol. 2003 Apr;4(4):355-60
references.pmid: 12640450
references.citation: Annu Rev Immunol. 2008;26:453-79
references.pmid: 18062768
references.citation: Nature. 2006 Dec 7;444(7120):724-9
references.pmid: 17086201
references.citation: Immunity. 2003 Apr;18(4):475-87
references.pmid: 12705851
references.citation: Nat Med. 2000 Mar;6(3):343-5
references.pmid: 10700239
references.citation: Nat Rev Immunol. 2005 Oct;5(10):772-82
references.pmid: 16200080
references.citation: Cell. 1994 Jan 14;76(1):17-27
references.pmid: 8287475
references.citation: Genes Immun. 2011 Mar;12(2):116-25
references.pmid: 21179116
references.citation: Eur J Immunol. 1994 Oct;24(10):2452-6
references.pmid: 7925574
references.citation: J Immunol. 2003 Nov 1;171(9):4493-503
references.pmid: 14568922
references.citation: Blood. 2004 May 1;103(9):3457-64
references.pmid: 14726372
references.citation: Immunity. 2000 May;12(5):537-46
references.pmid: 10843386
references.citation: Mol Cell Biol. 2007 Mar;27(6):2166-79
references.pmid: 17210636
references.citation: Nature. 1990 Jul 5;346(6279):66-8
references.pmid: 2164155
references.citation: Nature. 2009 Mar 12;458(7235):211-4
references.pmid: 19182777
references.citation: Cell. 1992 Aug 21;70(4):585-93
references.pmid: 1505025
references.citation: Immunity. 2007 Sep;27(3):425-37
references.pmid: 17719247
references.citation: Annu Rev Immunol. 2009;27:591-619
references.pmid: 19132916
references.citation: J Immunol. 2004 Jan 1;172(1):40-4
references.pmid: 14688307
references.citation: Cell. 1989 Sep 22;58(6):1055-65
references.pmid: 2550143
references.citation: Mol Cell Biol. 1998 Mar;18(3):1622-34
references.pmid: 9488479
references.citation: Semin Immunol. 2006 Aug;18(4):207-13
references.pmid: 16697661
references.citation: Proc Natl Acad Sci U S A. 1989 Aug;86(16):6302-6
references.pmid: 2548204
references.citation: Immunity. 2001 Jun;14(6):669-80
references.pmid: 11420038
references.citation: Cell Metab. 2011 Nov 2;14(5):684-99
references.pmid: 22000926
references.citation: Immunity. 2001 Jul;15(1):59-70
references.pmid: 11485738
references.citation: Science. 2004 Jan 30;303(5658):685-9
references.pmid: 14752163
references.citation: Immunity. 2010 Mar 26;32(3):342-54
references.pmid: 20346773
references.citation: Immunity. 2009 Oct 16;31(4):621-31
references.pmid: 19833087
references.citation: J Exp Med. 2003 Apr 21;197(8):1007-16
references.pmid: 12707300
references.citation: Nat Immunol. 2005 Mar;6(3):253-60
references.pmid: 15696169
references.citation: Immunity. 2010 Feb 26;32(2):163-74
references.pmid: 20137987
references.citation: J Exp Med. 1997 Aug 29;186(5):683-93
references.pmid: 9271584
references.citation: Immunity. 2000 Mar;12(3):313-22
references.pmid: 10755618
references.citation: Nat Genet. 2010 Jun;42(6):530-5
references.pmid: 20473312
references.citation: N Engl J Med. 2008 Dec 25;359(26):2767-77
references.pmid: 19073967
references.citation: Nature. 1992 May 14;357(6374):161-4
references.pmid: 1579166
references.citation: J Immunol. 1999 Feb 15;162(4):1879-83
references.pmid: 9973453
references.citation: J Immunol. 2007 Aug 15;179(4):2250-60
references.pmid: 17675486
references.citation: Oncogene. 2004 Oct 18;23(48):7990-8000
references.pmid: 15489916
references.citation: Science. 2000 Oct 6;290(5489):127-31
references.pmid: 11021796
references.citation: J Exp Med. 2008 Mar 17;205(3):625-40
references.pmid: 18316415
references.citation: J Exp Med. 1992 Dec 1;176(6):1733-8
references.pmid: 1334117
references.citation: Immunol Rev. 2009 Mar;228(1):9-22
references.pmid: 19290918
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13729-34
references.pmid: 12374859
references.citation: Science. 1990 Feb 23;247(4945):964-7
references.pmid: 1968289
references.citation: J Biol Chem. 2001 Jun 22;276(25):23173-8
references.pmid: 11294838
references.citation: Nat Immunol. 2003 Mar;4(3):248-54
references.pmid: 12577055
references.citation: Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9624-9
references.pmid: 8790380
references.citation: Int Immunol. 1999 Dec;11(12):1999-2014
references.pmid: 10590266
references.citation: Immunol Rev. 2009 Mar;228(1):41-57
references.pmid: 19290920
references.citation: J Immunol. 2002 Sep 15;169(6):2997-3005
references.pmid: 12218114
references.citation: J Autoimmun. 2010 Feb;34(1):45-54
references.pmid: 19744827
references.citation: Mol Cell Biol. 2006 Nov;26(22):8655-65
references.pmid: 16966372
references.citation: Nat Genet. 2007 Jul;39(7):857-64
references.pmid: 17554260
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16388-93
references.pmid: 17060632
references.citation: J Immunol. 2010 Sep 15;185(6):3256-67
references.pmid: 20696858
references.citation: Mol Endocrinol. 2002 Jan;16(1):58-69
references.pmid: 11773439