Xie et al. used Antigen-TCR Pairing and Multiomic Analysis of T cells (APMAT), an integrated experimental computational framework, to capture and analyze SARS-CoV-2-specific CD8+ T cells from 62 HLA A*02:01 participants infected with COVID-19. This framework enabled single-cell profiling and pairing of antigens, TCR sequences, and transcriptomes. APMAT revealed that distinct combinations of physicochemical properties of peptide antigens and TCR CDR3β sequences were strongly associated with T cell phenotypes and persistence. Integrated peptide–TCR analysis revealed phenotype-orchestrating interactions and divergent T cell fates over time.
Contributed by Shishir Pant
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.
Author Info: (1) Institute for Systems Biology, Seattle, WA, 98109, USA. Molecular Engineering & Sciences Institute, University of Washington, Seattle, WA, 98195, USA. (2) Institute for Systems
Author Info: (1) Institute for Systems Biology, Seattle, WA, 98109, USA. Molecular Engineering & Sciences Institute, University of Washington, Seattle, WA, 98195, USA. (2) Institute for Systems Biology, Seattle, WA, 98109, USA. Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA. (3) Institute for Systems Biology, Seattle, WA, 98109, USA. (4) Institute for Systems Biology, Seattle, WA, 98109, USA. Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA. (5) Institute for Systems Biology, Seattle, WA, 98109, USA. Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA. (6) Institute for Systems Biology, Seattle, WA, 98109, USA. Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA. (7) Institute for Systems Biology, Seattle, WA, 98109, USA. (8) Institute for Systems Biology, Seattle, WA, 98109, USA. (9) Institute for Systems Biology, Seattle, WA, 98109, USA. (10) Institute for Systems Biology, Seattle, WA, 98109, USA. (11) Institute for Systems Biology, Seattle, WA, 98109, USA. (12) Institute for Systems Biology, Seattle, WA, 98109, USA. (13) Institute for Systems Biology, Seattle, WA, 98109, USA. (14) Institute for Systems Biology, Seattle, WA, 98109, USA. (15) Institute for Systems Biology, Seattle, WA, 98109, USA. (16) Institute for Systems Biology, Seattle, WA, 98109, USA. (17) Institute for Systems Biology, Seattle, WA, 98109, USA. (18) Department of Medicine, Allergy and Infectious Diseases, University of Washington, Seattle, WA, 98109, USA. (19) Department of Medicine, Allergy and Infectious Diseases, University of Washington, Seattle, WA, 98109, USA. (20) Institute for Systems Biology, Seattle, WA, 98109, USA. (21) Providence Health & Services, Seattle, WA, 99109, USA. (22) Providence Health & Services, Seattle, WA, 99109, USA. Providence Swedish Medical Center, Seattle, WA, 98122, USA. (23) Providence Health & Services, Seattle, WA, 99109, USA. Providence Swedish Medical Center, Seattle, WA, 98122, USA. (24) Institute for Systems Biology, Seattle, WA, 98109, USA. (25) Department of Medicine, Allergy and Infectious Diseases, University of Washington, Seattle, WA, 98109, USA. (26) Providence Swedish Medical Center, Seattle, WA, 98122, USA. (27) Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA. Department of Medicine, Allergy and Infectious Diseases, University of Washington, Seattle, WA, 98109, USA. Department of Immunology, University of Washington, Seattle, WA, 98109, USA. (28) Department of Medicine, Allergy and Infectious Diseases, University of Washington, Seattle, WA, 98109, USA. (29) Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA. Department of Medicine, Allergy and Infectious Diseases, University of Washington, Seattle, WA, 98109, USA. Providence Health & Services, Seattle, WA, 99109, USA. Providence Swedish Medical Center, Seattle, WA, 98122, USA. (30) Institute for Systems Biology, Seattle, WA, 98109, USA. Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA. (31) Institute for Systems Biology, Seattle, WA, 98109, USA. jheath@isbscience.org.
