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

Alexander M Xu; William Chour; Diana C DeLucia; Yapeng Su; Ana Jimena Pavlovitch-Bedzyk; Rachel Ng; Yusuf Rasheed; Mark M Davis; John K Lee; James R Heath

doi:10.1016/j.cels.2023.03.001

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

Cell Syst. 2023 Apr 19;14(4):273-284.e5. doi: 10.1016/j.cels.2023.03.001. Epub 2023 Mar 30.

Authors

Affiliations

¹ Institute for Systems Biology, Seattle, WA 98109, USA; Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: alexander.xu@cshs.org.
² Institute for Systems Biology, Seattle, WA 98109, USA; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Keck School of Medicine, University of Southern California, Los Angeles, CA 91125, USA.
³ Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁴ Institute for Systems Biology, Seattle, WA 98109, USA; Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
⁵ Computational and Systems Immunology Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁶ Institute for Systems Biology, Seattle, WA 98109, USA.
⁷ Computational and Systems Immunology Program, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁸ Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
⁹ Institute for Systems Biology, Seattle, WA 98109, USA. Electronic address: jim.heath@isbscience.org.

Abstract

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.

Keywords: CDR3 domains; SARS-COV-2; T cell receptors; T cells; antigens.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Antigens
Entropy
Receptors, Antigen, T-Cell*
Receptors, Antigen, T-Cell, alpha-beta* / genetics

Substances

Receptors, Antigen, T-Cell, alpha-beta
Receptors, Antigen, T-Cell
Antigens

Abstract

Publication types

MeSH terms

Substances

Grants and funding