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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...

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Detalles Bibliográficos
Autores principales: Leddy, Owen, White, Forest M, Bryson, Bryan D
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
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.
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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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