Immunopeptidomics reveals determinants of Mycobacterium tuberculosis antigen presentation on MHC class I
- Massachusetts Institute of Technology, United States
Abstract
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.
Data availability
The mass spectrometry data have been deposited to the ProteomeXchange Consortium via the PRIDE (Perez-Riverol et al., 2022) partner repository with the dataset identifiers PXD037837 (DDA data) and PXD037843 (SureQuant data). Microscopy data analysis scripts are available on GitHub at https://github.com/oleddy/local_correlation_analysis.
Article and author information
Author details
Funding
National Institutes of Health (R35GM142900-01)
- Owen Leddy
- Bryan D Bryson
National Institutes of Health (R01A1022553)
- Owen Leddy
- Bryan D Bryson
National Institute of Environmental Health Sciences (P42 ES027707)
- Owen Leddy
- Forest M White
Center for Precision Cancer Medicine
- Owen Leddy
- Forest M White
National Institutes of Health (P30 AI06035)
- Owen Leddy
- Bryan D Bryson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Leddy et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,630
- views
-
- 492
- downloads
-
- 25
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Citations by DOI
-
- 25
- citations for umbrella DOI https://doi.org/10.7554/eLife.84070
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Immunopeptidomics reveals determinants of Mycobacterium tuberculosis antigen presentation on MHC class I
eLife 12:e84070.
https://doi.org/10.7554/eLife.84070
