title: Kinetics of antigen expression and epitope presentation during virus infection.
abstract: Current knowledge about the dynamics of antigen presentation to T cells during viral infection is very poor despite being of fundamental importance to our understanding of anti-viral immunity. Here we use an advanced mass spectrometry method to simultaneously quantify the presentation of eight vaccinia virus peptide-MHC complexes (epitopes) on infected cells and the amounts of their source antigens at multiple times after infection. The results show a startling 1000-fold range in abundance as well as strikingly different kinetics across the epitopes monitored. The tight correlation between onset of protein expression and epitope display for most antigens provides the strongest support to date that antigen presentation is largely linked to translation and not later degradation of antigens. Finally, we show a complete disconnect between the epitope abundance and immunodominance hierarchy of these eight epitopes. This study highlights the complexity of viral antigen presentation by the host and demonstrates the weakness of simple models that assume total protein levels are directly linked to epitope presentation and immunogenicity.
authors: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors: Nathan P
authors: NP
authors: Croft
authors: Stewart A
authors: SA
authors: Smith
authors: Yik Chun
authors: YC
authors: Wong
authors: Chor Teck
authors: CT
authors: Tan
authors: Nadine L
authors: NL
authors: Dudek
authors: Inge E A
authors: IE
authors: Flesch
authors: Leon C W
authors: LC
authors: Lin
authors: David C
authors: DC
authors: Tscharke
authors: Anthony W
authors: AW
authors: Purcell
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology*; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology*; D054884:Host-Pathogen Interactions; D007700:Kinetics; D008285:Major Histocompatibility Complex / Q000276:immunology; D013058:Mass Spectrometry; D051379:Mice; D012899:Smallpox / Q000276:immunology*; D014616:Vaccinia virus / Q000276:immunology*; D014764:Viral Proteins / Q000737:chemistry / Q000276:immunology; D014777:Virus Diseases / Q000276:immunology*
chemical_list: D000939:Epitopes; D014764:Viral Proteins
references: J Immunol. 2002 Jun 1;168(11):5403-8
references: 12023332
references: Immunity. 1997 Jun;6(6):715-26
references: 9208844
references: Nat Immunol. 2002 Mar;3(3):265-71
references: 11828323
references: Proc Natl Acad Sci U S A. 2012 Mar 20;109(12):4580-5
references: 22403068
references: J Immunol. 2004 Jun 1;172(11):6666-74
references: 15153482
references: Mol Cell Proteomics. 2007 Jan;6(1):102-13
references: 17074750
references: Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2140-5
references: 18245380
references: Mol Syst Biol. 2011 Sep 27;7:533
references: 21952136
references: Eur J Immunol. 2010 Jun;40(6):1552-65
references: 20306470
references: Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11513-8
references: 20534518
references: J Immunol. 2004 Jul 1;173(1):402-9
references: 15210799
references: Cold Spring Harb Symp Quant Biol. 1989;54 Pt 1:299-308
references: 2484163
references: Nat Biotechnol. 2006 Jul;24(7):817-9
references: 16767078
references: J Exp Med. 2008 Mar 17;205(3):595-610
references: 18299400
references: J Immunol. 1997 Mar 15;158(6):2723-30
references: 9058806
references: Nature. 1990 Aug 2;346(6283):476-80
references: 2198471
references: Curr Pharm Des. 2010;16(28):3149-57
references: 20687873
references: Proc Natl Acad Sci U S A. 2012 May 1;109(18):7025-30
references: 22509014
references: Immunity. 2006 Oct;25(4):533-43
references: 17046682
references: Nat Rev Immunol. 2011 Nov 11;11(12):823-36
references: 22076556
references: Blood. 2012 Jun 28;119(26):e181-91
references: 22438248
references: Proteomics. 2011 Jun;11(11):2336-40
references: 21598389
references: J Immunol. 2001 Jan 15;166(2):1016-27
references: 11145681
references: Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11737-42
references: 15286279
references: J Exp Med. 2005 Jan 3;201(1):95-104
references: 15623576
references: Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):6964-9
references: 20351281
references: Cell Mol Life Sci. 2011 May;68(9):1481-9
references: 21416150
references: Mol Syst Biol. 2008;4:222
references: 18854821
references: J Immunol. 1996 Sep 1;157(5):1823-6
references: 8757297
references: J Exp Med. 2004 Jan 5;199(1):131-6
references: 14699084
references: J Exp Med. 2005 Nov 7;202(9):1191-7
references: 16260488
references: J Exp Med. 2001 Jun 4;193(11):1319-26
references: 11390439
references: J Exp Med. 2007 Sep 3;204(9):2187-98
references: 17709425
references: Nature. 1992 Aug 27;358(6389):764-8
references: 1380674
references: PLoS Pathog. 2010 Feb 12;6(2):e1000768
references: 20169189
references: Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9319-24
references: 18591662
references: Science. 1992 Mar 6;255(5049):1261-3
references: 1546328
references: Eur J Immunol. 2000 Apr;30(4):1172-81
references: 10760807
references: Immunity. 2003 Mar;18(3):343-54
references: 12648452
references: J Immunol. 2003 Jul 1;171(1):22-6
references: 12816978
references: J Virol. 2010 Oct;84(19):10220-9
references: 20668091
references: J Immunol. 2001 Nov 1;167(9):4801-4
references: 11673482
references: Nature. 1991 Oct 17;353(6345):622-7
references: 1656276
references: Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1534-8
references: 8108441
references: Mol Cell Proteomics. 2005 Aug;4(8):1134-44
references: 15923565
references: Cancer Immunol Immunother. 2005 Apr;54(4):359-71
references: 15378283
references: J Immunol Methods. 2006 Apr 20;311(1-2):12-8
references: 16516224
references: J Mol Med (Berl). 2009 Nov;87(11):1045-51
references: 19763524
references: Diabetes. 2012 Nov;61(11):3018-25
references: 22872234
references: J Immunol. 2011 Feb 15;186(4):2065-72
references: 21228349
references: Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):16998-7003
references: 23027972
references: J Proteome Res. 2009 Jul;8(7):3746-51
references: 19405522
references: Science. 2004 May 28;304(5675):1318-21
references: 15166379
references: Nature. 2000 Apr 13;404(6779):770-4
references: 10783891
references: Nat Immunol. 2008 Feb;9(2):155-65
references: 18193049
references: J Immunol. 2010 Jan 1;184(1):45-55
references: 19949110
references: Nature. 1996 May 9;381(6578):166-8
references: 8610016
references: Immunity. 2000 Jan;12(1):83-93
references: 10661408
references: Curr Opin Immunol. 2008 Feb;20(1):75-81
references: 18243674
references: Mol Immunol. 2012 Jun;51(2):136-42
references: 22424782
references: Bioinformatics. 2010 Apr 1;26(7):966-8
references: 20147306
references: J Immunol. 1997 Mar 15;158(6):2535-42
references: 9058784
references: Mol Cell Proteomics. 2006 Feb;5(2):357-65
references: 16272561
references: Nat Methods. 2009 May;6(5):359-62
references: 19377485
references: Nat Immunol. 2011 Dec 25;13(2):129-35
references: 22197977
references: Proc Natl Acad Sci U S A. 1982 Aug;79(15):4737-41
references: 6181513
references: Immunol Rev. 2005 Oct;207:8-18
references: 16181323
references: J Virol. 2011 Oct;85(19):9899-908
references: 21795349
references: Trends Immunol. 2011 Nov;32(11):548-58
references: 21962745
references: J Immunol. 2000 Jun 15;164(12):6120-9
references: 10843661
references: PLoS One. 2012;7(6):e39533
references: 22745779
references: Nat Rev Drug Discov. 2007 May;6(5):404-14
references: 17473845
references: Nature. 2000 Apr 13;404(6779):774-8
references: 10783892
references: Nature. 2011 May 19;473(7347):337-42
references: 21593866
references: Eur J Immunol. 2009 Mar;39(3):717-22
references: 19224639
references: J Immunol. 2010 Sep 1;185(5):2763-72
references: 20660711
references: Nat Rev Immunol. 2008 Aug;8(8):607-18
references: 18641646
references: Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11572-7
references: 21709220
references: J Clin Invest. 2010 Jun;120(6):1885-94
references: 20440073
references: J Immunol. 1996 May 1;156(9):3308-14
references: 8617954
references: Mol Immunol. 2003 Jan;39(10):567-75
references: 12431390
references: J Immunol. 2008 Aug 1;181(3):2124-33
references: 18641351
references: J Immunol. 2009 May 15;182(10):6328-41
references: 19414786
references: Immunity. 2008 Jun;28(6):859-69
references: 18499487
references: Science. 1994 Apr 29;264(5159):716-9
references: 7513441
references: Autoimmun Rev. 2012 Jul;11(9):627-35
references: 22100331