Targeting infection-specific peptides in immunopeptidomics studies for vaccine target discovery
Name
jem_20250444.pdf
Description
Published version
Size
5.15 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Leddy, Owen
Yuki, Yuko
Carrington, Mary
Bryson, Bryan D
White, Forest M
Date Issued
October 6, 2025
Journal
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Citation
Owen Leddy, Yuko Yuki, Mary Carrington, Bryan D. Bryson, Forest M. White; Targeting infection-specific peptides in immunopeptidomics studies for vaccine target discovery. J Exp Med 6 October 2025; 222 (10): e20250444.
Version
Final published version
Abstract
Vaccine-elicited T cell responses can contribute to immune protection against emerging infectious disease risks such as antimicrobial-resistant (AMR) microbial pathogens and viruses with pandemic potential, but rapidly identifying appropriate targets for T cell priming vaccines remains challenging. Mass spectrometry (MS) analysis of peptides presented on MHCs can identify potential targets for protective T cell responses in a proteome-wide manner. However, pathogen-derived peptides are outnumbered by self-peptides in the MHC repertoire and may be missed in untargeted MS analyses. Here, we present a novel approach, termed PathMHC, that uses computational analysis of untargeted MS data followed by targeted MS to discover novel pathogen-derived MHC peptides more efficiently than untargeted methods alone. We applied this workflow to identify MHC peptides derived from multiple microbes, including potential vaccine targets presented on MHC-I by human dendritic cells infected with Mycobacterium tuberculosis (Mtb), finding that all Mtb peptides detected in the MHC-I repertoire derived from proteins exported by type VII secretion systems. PathMHC will facilitate antigen discovery campaigns for vaccine development.
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DOI of Published Version
https://doi.org/10.1084/jem.20250444
