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Immunopeptidomics reveals determinants of Mycobacterium tuberculosis antigen presentation on MHC class I
CD8+ T cell recognition of Mycobacterium tuberculosis (Mtb)-specific peptides presented on major histocompatibility complex class I (MHC-I) contributes to immunity to tuberculosis (TB), but the principles that govern presentation of Mtb antigens on MHC-I are incompletely understood. In this study, m...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10159623/ https://www.ncbi.nlm.nih.gov/pubmed/37073954 http://dx.doi.org/10.7554/eLife.84070 |
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author | Leddy, Owen White, Forest M Bryson, Bryan D |
author_facet | Leddy, Owen White, Forest M Bryson, Bryan D |
author_sort | Leddy, Owen |
collection | PubMed |
description | CD8+ T cell recognition of Mycobacterium tuberculosis (Mtb)-specific peptides presented on major histocompatibility complex class I (MHC-I) contributes to immunity to tuberculosis (TB), but the principles that govern presentation of Mtb antigens on MHC-I are incompletely understood. In this study, mass spectrometry (MS) analysis of the MHC-I repertoire of Mtb-infected primary human macrophages reveals that substrates of Mtb’s type VII secretion systems (T7SS) are overrepresented among Mtb-derived peptides presented on MHC-I. Quantitative, targeted MS shows that ESX-1 activity is required for presentation of Mtb peptides derived from both ESX-1 substrates and ESX-5 substrates on MHC-I, consistent with a model in which proteins secreted by multiple T7SSs access a cytosolic antigen processing pathway via ESX-1-mediated phagosome permeabilization. Chemical inhibition of proteasome activity, lysosomal acidification, or cysteine cathepsin activity did not block presentation of Mtb antigens on MHC-I, suggesting involvement of other proteolytic pathways or redundancy among multiple pathways. Our study identifies Mtb antigens presented on MHC-I that could serve as targets for TB vaccines, and reveals how the activity of multiple T7SSs interacts to contribute to presentation of Mtb antigens on MHC-I. |
format | Online Article Text |
id | pubmed-10159623 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-101596232023-05-05 Immunopeptidomics reveals determinants of Mycobacterium tuberculosis antigen presentation on MHC class I Leddy, Owen White, Forest M Bryson, Bryan D eLife Immunology and Inflammation CD8+ T cell recognition of Mycobacterium tuberculosis (Mtb)-specific peptides presented on major histocompatibility complex class I (MHC-I) contributes to immunity to tuberculosis (TB), but the principles that govern presentation of Mtb antigens on MHC-I are incompletely understood. In this study, mass spectrometry (MS) analysis of the MHC-I repertoire of Mtb-infected primary human macrophages reveals that substrates of Mtb’s type VII secretion systems (T7SS) are overrepresented among Mtb-derived peptides presented on MHC-I. Quantitative, targeted MS shows that ESX-1 activity is required for presentation of Mtb peptides derived from both ESX-1 substrates and ESX-5 substrates on MHC-I, consistent with a model in which proteins secreted by multiple T7SSs access a cytosolic antigen processing pathway via ESX-1-mediated phagosome permeabilization. Chemical inhibition of proteasome activity, lysosomal acidification, or cysteine cathepsin activity did not block presentation of Mtb antigens on MHC-I, suggesting involvement of other proteolytic pathways or redundancy among multiple pathways. Our study identifies Mtb antigens presented on MHC-I that could serve as targets for TB vaccines, and reveals how the activity of multiple T7SSs interacts to contribute to presentation of Mtb antigens on MHC-I. eLife Sciences Publications, Ltd 2023-04-19 /pmc/articles/PMC10159623/ /pubmed/37073954 http://dx.doi.org/10.7554/eLife.84070 Text en © 2023, Leddy et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Immunology and Inflammation Leddy, Owen White, Forest M Bryson, Bryan D Immunopeptidomics reveals determinants of Mycobacterium tuberculosis antigen presentation on MHC class I |
title | Immunopeptidomics reveals determinants of Mycobacterium tuberculosis antigen presentation on MHC class I |
title_full | Immunopeptidomics reveals determinants of Mycobacterium tuberculosis antigen presentation on MHC class I |
title_fullStr | Immunopeptidomics reveals determinants of Mycobacterium tuberculosis antigen presentation on MHC class I |
title_full_unstemmed | Immunopeptidomics reveals determinants of Mycobacterium tuberculosis antigen presentation on MHC class I |
title_short | Immunopeptidomics reveals determinants of Mycobacterium tuberculosis antigen presentation on MHC class I |
title_sort | immunopeptidomics reveals determinants of mycobacterium tuberculosis antigen presentation on mhc class i |
topic | Immunology and Inflammation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10159623/ https://www.ncbi.nlm.nih.gov/pubmed/37073954 http://dx.doi.org/10.7554/eLife.84070 |
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