title: Sculpting MHC class II-restricted self and non-self peptidome by the class I Ag-processing machinery and its impact on Th-cell responses.
abstract: It is generally assumed that the MHC class I antigen (Ag)-processing (CAP) machinery - which supplies peptides for presentation by class I molecules - plays no role in class II-restricted presentation of cytoplasmic Ags. In striking contrast to this assumption, we previously reported that proteasome inhibition, TAP deficiency or ERAAP deficiency led to dramatically altered T helper (Th)-cell responses to allograft (HY) and microbial (Listeria monocytogenes) Ags. Herein, we tested whether altered Ag processing and presentation, altered CD4(+) T-cell repertoire, or both underlay the above finding. We found that TAP deficiency and ERAAP deficiency dramatically altered the quality of class II-associated self peptides suggesting that the CAP machinery impacts class II-restricted Ag processing and presentation. Consistent with altered self peptidomes, the CD4(+) T-cell receptor repertoire of mice deficient in the CAP machinery substantially differed from that of WT animals resulting in altered CD4(+) T-cell Ag recognition patterns. These data suggest that TAP and ERAAP sculpt the class II-restricted peptidome, impacting the CD4(+) T-cell repertoire, and ultimately altering Th-cell responses. Together with our previous findings, these data suggest multiple CAP machinery components sequester or degrade MHC class II-restricted epitopes that would otherwise be capable of eliciting functional Th-cell responses.
authors: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA. ctspencer@utep.edu
authors: Charles T
authors: CT
authors: Spencer
authors: Srdjan M
authors: SM
authors: Dragovic
authors: Stephanie B
authors: SB
authors: Conant
authors: Jennifer J
authors: JJ
authors: Gray
authors: Mu
authors: M
authors: Zheng
authors: Parimal
authors: P
authors: Samir
authors: Xinnan
authors: X
authors: Niu
authors: Magdalini
authors: M
authors: Moutaftsi
authors: Luc
authors: L
authors: Van Kaer
authors: Alessandro
authors: A
authors: Sette
authors: Andrew J
authors: AJ
authors: Link
authors: Sebastian
authors: S
authors: Joyce
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D007931:Leucyl Aminopeptidase / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D040901:Proteomics; D020539:Sequence Analysis, Protein; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D000950:Antigens, Ly; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D010446:Peptide Fragments; D007931:Leucyl Aminopeptidase; C456799:puromycin-insensitive leucyl-specific aminopeptidase
references: J Immunol. 2011 Dec 15;187(12):6335-45
references: 22084435
references: Ann N Y Acad Sci. 1995 Jul 7;756:19-27
references: 7645828
references: J Immunol. 2005 Feb 15;174(4):1811-9
references: 15699107
references: Curr Opin Immunol. 2004 Feb;16(1):96-102
references: 14734116
references: Eur J Pediatr. 1990 Jul;149(10):700-4
references: 2209663
references: J Immunol. 2007 Jun 1;178(11):6814-20
references: 17513729
references: J Exp Med. 1993 Dec 1;178(6):2173-83
references: 8245790
references: Nat Immunol. 2006 Jan;7(1):103-12
references: 16299505
references: Mol Immunol. 2011 Mar;48(6-7):835-45
references: 21292324
references: Am J Hum Genet. 1999 Aug;65(2):279-86
references: 10417269
references: J Proteome Res. 2011 Nov 4;10(11):5016-30
references: 21913724
references: Science. 1994 Jul 8;265(5169):237-41
references: 7517574
references: J Exp Med. 2000 May 1;191(9):1513-24
references: 10790426
references: J Virol. 2011 Mar;85(5):2351-63
references: 21159875
references: J Immunol. 2012 Oct 1;189(7):3538-47
references: 22925930
references: J Exp Med. 2007 Oct 29;204(11):2591-602
references: 17923502
references: J Am Soc Mass Spectrom. 1994 Nov;5(11):976-89
references: 24226387
references: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D213-7
references: 16381849
references: Cell. 1992 Dec 24;71(7):1205-14
references: 1473153
references: Eur J Immunol. 1999 Jan;29(1):119-31
references: 9933093
references: Eur J Immunol. 1995 Jan;25(1):48-53
references: 7843252
references: J Immunol. 2010 Mar 15;184(6):3033-42
references: 20173027
references: Eur J Immunol. 2001 May;31(5):1485-94
references: 11465105
references: Immunity. 2010 Mar 26;32(3):298-9
references: 20346769
references: Hum Immunol. 1996 Sep 15;50(1):70-7
references: 8872177
references: J Leukoc Biol. 2005 Jan;77(1):24-32
references: 15496448
references: J Exp Med. 2006 Mar 20;203(3):647-59
references: 16505142
references: Mol Cell Proteomics. 2006 Aug;5(8):1497-513
references: 16707483
references: J Immunol. 2003 Dec 15;171(12):6502-9
references: 14662850
references: J Immunol. 2001 Sep 1;167(5):2632-41
references: 11509605
references: Genes Chromosomes Cancer. 2009 May;48(5):410-8
references: 19202550
references: J Exp Med. 1996 Mar 1;183(3):1063-9
references: 8642248
references: Immunity. 2010 Feb 26;32(2):227-39
references: 20171125
references: Traffic. 2008 Jan;9(1):10-6
references: 17916226
references: Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1464-9
references: 8643655
references: J Immunol. 2009 Mar 15;182(6):3335-41
references: 19265109
references: Immunity. 1994 Oct;1(7):585-94
references: 7600287
references: Immunity. 2007 Jan;26(1):79-92
references: 17182262
references: Clin Cancer Res. 2009 Feb 1;15(3):1019-23
references: 19188174
references: Mol Cell Proteomics. 2007 Jun;6(6):1049-58
references: 17327219
references: J Immunol. 2004 Mar 15;172(6):3469-79
references: 15004147
references: Nature. 1991 Oct 17;353(6345):622-7
references: 1656276
references: J Immunol. 1993 Dec 15;151(12):6751-6
references: 8258689
references: Proc Natl Acad Sci U S A. 1992 May 1;89(9):3932-6
references: 1570316
references: Eur J Immunol. 2003 May;33(5):1250-9
references: 12731050
references: Hum Genet. 2009 Nov;126(5):655-66
references: 19578876
references: Immunol Rev. 1994 Apr;138:207-21
references: 8070816
references: Eur J Immunol. 1995 Dec;25(12):3402-11
references: 8566030
references: Science. 2005 Jan 28;307(5709):593-6
references: 15591165
references: J Biol Chem. 2007 Dec 28;282(52):37836-43
references: 17977821
references: J Immunol. 2011 Mar 15;186(6):3594-605
references: 21296983
references: J Immunol. 2003 Dec 15;171(12):6510-8
references: 14662851
references: J Clin Invest. 1995 Jul;96(1):217-23
references: 7615790
references: Nature. 1992 Jun 25;357(6380):702-4
references: 1614517
references: Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14692-7
references: 8962116
references: Nat Immunol. 2007 Jan;8(1):101-8
references: 17128277
references: J Exp Med. 1993 Jul 1;178(1):73-85
references: 8315396
references: J Cell Sci. 2004 Aug 15;117(Pt 18):4219-30
references: 15316082
references: J Immunol. 2012 Sep 1;189(5):2383-92
references: 22837489
references: Proc Natl Acad Sci U S A. 1993 May 1;90(9):4319-23
references: 8483950
references: J Immunol. 2011 Jun 15;186(12):6683-92
references: 21572029
references: J Exp Med. 1990 Sep 1;172(3):947-54
references: 2388037
references: Proc Natl Acad Sci U S A. 1994 May 10;91(10):4145-9
references: 8183884
references: Expert Rev Mol Med. 2004 Mar 30;6(8):1-14
references: 15061872
references: J Virol. 2011 Apr;85(7):3473-85
references: 21248040
references: Immunity. 2005 May;22(5):571-81
references: 15894275
references: J Virol. 1989 Apr;63(4):1756-62
references: 2784508
references: Clin Exp Immunol. 2001 Aug;125(2):274-82
references: 11529920
references: Hum Pathol. 2010 Dec;41(12):1758-69
references: 20869097
references: Nat Immunol. 2005 Mar;6(3):287-94
references: 15711549
references: Immunol Rev. 2005 Oct;207:145-57
references: 16181333
references: J Immunol. 2008 Oct 1;181(7):4471-84
references: 18802050