Document Detail


Sculpting MHC class II-restricted self and non-self peptidome by the class I Ag-processing machinery and its impact on Th-cell responses.
MedLine Citation:
PMID:  23386199     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Charles T Spencer; Srdjan M Dragovic; Stephanie B Conant; Jennifer J Gray; Mu Zheng; Parimal Samir; Xinnan Niu; Magdalini Moutaftsi; Luc Van Kaer; Alessandro Sette; Andrew J Link; Sebastian Joyce
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-03-05
Journal Detail:
Title:  European journal of immunology     Volume:  43     ISSN:  1521-4141     ISO Abbreviation:  Eur. J. Immunol.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-25     Completed Date:  2013-06-17     Revised Date:  2014-04-02    
Medline Journal Info:
Nlm Unique ID:  1273201     Medline TA:  Eur J Immunol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  1162-72     Citation Subset:  IM    
Copyright Information:
© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Antigen Presentation*
Antigen-Presenting Cells / cytology,  immunology*,  metabolism
Antigens, Ly / genetics,  immunology
Epitopes / chemistry,  immunology
Histocompatibility Antigens Class I / genetics,  immunology*
Histocompatibility Antigens Class II / genetics,  immunology*
Leucyl Aminopeptidase / deficiency,  genetics,  immunology
Membrane Proteins / deficiency,  genetics,  immunology
Mice
Mice, Knockout
Molecular Sequence Data
Peptide Fragments / chemistry,  immunology
Proteomics
Sequence Analysis, Protein
T-Lymphocytes, Helper-Inducer / cytology,  immunology*,  metabolism
Tandem Mass Spectrometry
Grant Support
ID/Acronym/Agency:
AI040024/AI/NIAID NIH HHS; AI040079/AI/NIAID NIH HHS; CA068485/CA/NCI NIH HHS; DK058404/DK/NIDDK NIH HHS; G12MD007592/MD/NIMHD NIH HHS; HL054977/HL/NHLBI NIH HHS; HL069765/HL/NHLBI NIH HHS; N01AI40024/AI/NIAID NIH HHS; N01AI40079/AI/NIAID NIH HHS; P30 CA068485/CA/NCI NIH HHS; P30 DK058404/DK/NIDDK NIH HHS; R01 HL054977/HL/NHLBI NIH HHS; T32 HL069765/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, Ly; 0/Epitopes; 0/Histocompatibility Antigens Class I; 0/Histocompatibility Antigens Class II; 0/Ly6a protein, mouse; 0/Membrane Proteins; 0/Peptide Fragments; EC 3.4.11.1/Leucyl Aminopeptidase; EC 3.4.11.1/puromycin-insensitive leucyl-specific aminopeptidase

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