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APMAT analysis reveals the association between CD8 T cell receptors, cognate antigen, and T cell phenotype and persistence

Jingyi Xie, Daniel G. Chen, William Chour, Rachel H. Ng, Rongyu Zhang, Dan Yuan, Jongchan Choi, Michaela McKasson, Pamela Troisch, Brett Smith, Lesley Jones, Andrew Webster, Yusuf Rasheed, Sarah Li, Rick Edmark, Sunga Hong, Kim M. Murray, Jennifer K. Logue, Nicholas M. Franko, Christopher G. Lausted, Brian Piening, Heather Algren, Julie Wallick, Andrew T. Magis, Kino Watanabe, Phil Mease, Philip D. Greenberg, Helen Chu, Jason D. Goldman, Yapeng Su and James R. Heath ()
Additional contact information
Jingyi Xie: Institute for Systems Biology
Daniel G. Chen: Institute for Systems Biology
William Chour: Institute for Systems Biology
Rachel H. Ng: Institute for Systems Biology
Rongyu Zhang: Institute for Systems Biology
Dan Yuan: Institute for Systems Biology
Jongchan Choi: Institute for Systems Biology
Michaela McKasson: Institute for Systems Biology
Pamela Troisch: Institute for Systems Biology
Brett Smith: Institute for Systems Biology
Lesley Jones: Institute for Systems Biology
Andrew Webster: Institute for Systems Biology
Yusuf Rasheed: Institute for Systems Biology
Sarah Li: Institute for Systems Biology
Rick Edmark: Institute for Systems Biology
Sunga Hong: Institute for Systems Biology
Kim M. Murray: Institute for Systems Biology
Jennifer K. Logue: University of Washington
Nicholas M. Franko: University of Washington
Christopher G. Lausted: Institute for Systems Biology
Brian Piening: Providence Health & Services
Heather Algren: Providence Health & Services
Julie Wallick: Providence Health & Services
Andrew T. Magis: Institute for Systems Biology
Kino Watanabe: University of Washington
Phil Mease: Providence Swedish Medical Center
Philip D. Greenberg: Fred Hutchinson Cancer Center
Helen Chu: University of Washington
Jason D. Goldman: Fred Hutchinson Cancer Center
Yapeng Su: Institute for Systems Biology
James R. Heath: Institute for Systems Biology

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Elucidating the relationships between a class I peptide antigen, a CD8 T cell receptor (TCR) specific to that antigen, and the T cell phenotype that emerges following antigen stimulation, remains a mostly unsolved problem, largely due to the lack of large data sets that can be mined to resolve such relationships. Here, we describe Antigen-TCR Pairing and Multiomic Analysis of T-cells (APMAT), an integrated experimental-computational framework designed for the high-throughput capture and analysis of CD8 T cells, with paired antigen, TCR sequence, and single-cell transcriptome. Starting with 951 putative antigens representing a comprehensive survey of the SARS-CoV-2 viral proteome, we utilize APMAT for the capture and single cell analysis of CD8 T cells from 62 HLA A*02:01 COVID-19 participants. We leverage this comprehensive dataset to integrate with peptide antigen properties, TCR CDR3 sequences, and T cell phenotypes to show that distinct physicochemical features of the antigen-TCR pairs strongly associate with both T cell phenotype and T cell persistence. This analysis suggests that CD8 T cell phenotype following antigen stimulation is at least partially deterministic, rather than the result of stochastic biological properties.

Date: 2025
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DOI: 10.1038/s41467-025-56659-3

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