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Published April 19, 2023 | Published
Journal Article Open

Entropic analysis of antigen-specific CDR3 domains identifies essential binding motifs shared by CDR3s with different antigen specificities


Antigen-specific T cell receptor (TCR) sequences can have prognostic, predictive, and therapeutic value, but decoding the specificity of TCR recognition remains challenging. Unlike DNA strands that base pair, TCRs bind to their targets with different orientations and different lengths, which complicates comparisons. We present scanning parametrized by normalized TCR length (SPAN-TCR) to analyze antigen-specific TCR CDR3 sequences and identify patterns driving TCR-pMHC specificity. Using entropic analysis, SPAN-TCR identifies 2-mer motifs that decrease the diversity (entropy) of CDR3s. These motifs are the most common patterns that can predict CDR3 composition, and we identify "essential" motifs that decrease entropy in the same CDR3 α or β chain containing the 2-mer, and "super-essential" motifs that decrease entropy in both chains. Molecular dynamics analysis further suggests that these motifs may play important roles in binding. We then employ SPAN-TCR to resolve similarities in TCR repertoires against different antigens using public databases of TCR sequences.

Additional Information

© 2023 Elsevier Inc. We are grateful to all participants in this study and to the medical teams at the Swedish Medical Center for their support. We thank the Northwest Genomic Center and Fred Hutchinson Cancer Research Center for help with sequencing services and the ISB-Swedish COVID-19 Biobanking Unit. We thank the Fred Hutch Genomics Shared Resource (supported by the NIH/NCI Cancer Center Support grant P30 CA015704) and the WA State Andy Hill Care Fund. We thank Amazon Web Services for their support through cloud computing credits provided by the AWS Diagnostic Development Initiative (DDI). We acknowledge funding support from the Parker Institute for Cancer Immunotherapy (to J.R.H. and M.M.D.), Merck, the Biomedical Advanced Research and Development Authority (HHSO10201600031C to J.R.H. and M.M.D.), the Department of Defense Prostate Cancer Research Program (W81XWH-20-1-0119 to D.C.D. and J.K.L.), and the NIH (P50 CA097186 Developmental Research Program to J.K.L., 1 R01 CA264090-01 to J.R.H., and CTSIUL1TR001881 to A.M.X.). Data and code availability: Single-cell TCR-seq data have been deposited at GEO and are publicly available as of the date of publication. Accession numbers are listed in the key resources table. TCR sequence data was obtained from VDJdb, McPAS-TCR, TBAdb, and MIRA databases. Links are provided in the key resources table. All original code has been deposited at Github and is publicly available as of the date of publication. DOIs are listed in the key resources table. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. Author contributions: Conceptualization, A.M.X. and J.R.H.; methodology, A.M.X.; software, A.M.X., Y.R., and A.J.P.-B.; formal analysis, A.M.X. and A.J.P.-B.; data curation, A.M.X. and A.J.P.-B.; writing – original draft, A.M.X.; writing – review & editing, A.M.X. and J.R.H.; visualization, A.M.X. and Y.R.; supervision, J.R.H., M.M.D., and J.K.L.; investigation, W.C., D.C.D., Y.S., and R.N.; resources, W.C., D.C.D., Y.S., and R.N. Declaration of interests: J.R.H. is a founder and board member of Isoplexis and PACT Pharma. M.M.D. is a member of the Scientific Advisory Board of PACT Pharma.

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Additional details

April 19, 2024
April 19, 2024