title: T-cell receptor repertoires share a restricted set of public and abundant CDR3 sequences that are associated with self-related immunity.
abstract: The T-cell receptor (TCR) repertoire is formed by random recombinations of genomic precursor elements; the resulting combinatorial diversity renders unlikely extensive TCR sharing between individuals. Here, we studied CDR3β amino acid sequence sharing in a repertoire-wide manner, using high-throughput TCR-seq in 28 healthy mice. We uncovered hundreds of public sequences shared by most mice. Public CDR3 sequences, relative to private sequences, are two orders of magnitude more abundant on average, express restricted V/J segments, and feature high convergent nucleic acid recombination. Functionally, public sequences are enriched for MHC-diverse CDR3 sequences that were previously associated with autoimmune, allograft, and tumor-related reactions, but not with anti-pathogen-related reactions. Public CDR3 sequences are shared between mice of different MHC haplotypes, but are associated with different, MHC-dependent, V genes. Thus, despite their random generation process, TCR repertoires express a degree of uniformity in their post-genomic organization. These results, together with numerical simulations of TCR genomic rearrangements, suggest that biases and convergence in TCR recombination combine with ongoing selection to generate a restricted subset of self-associated, public CDR3 TCR sequences, and invite reexamination of the basic mechanisms of T-cell repertoire formation.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel;
authors.forename: Asaf
authors.initials: A
authors.lastname: Madi
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel;
authors.forename: Eric
authors.initials: E
authors.lastname: Shifrut
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel;
authors.forename: Shlomit
authors.initials: S
authors.lastname: Reich-Zeliger
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel;
authors.forename: Hilah
authors.initials: H
authors.lastname: Gal
authors.affiliation: Division of Infection and Immunity, The Cruciform Building, UCL, London WC1 6BT, United Kingdom.
authors.forename: Katharine
authors.initials: K
authors.lastname: Best
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel;
authors.forename: Wilfred
authors.initials: W
authors.lastname: Ndifon
authors.affiliation: Division of Infection and Immunity, The Cruciform Building, UCL, London WC1 6BT, United Kingdom.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Chain
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel; irun.cohen@weizmann.ac.il nir.friedman@weizmann.ac.il.
authors.forename: Irun R
authors.initials: IR
authors.lastname: Cohen
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel; irun.cohen@weizmann.ac.il nir.friedman@weizmann.ac.il.
authors.forename: Nir
authors.initials: N
authors.lastname: Friedman
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D005260:Female; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D059372:Nucleotide Motifs; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics* / Q000276:immunology; D017423:Sequence Analysis, RNA / Q000379:methods*; D060152:V(D)J Recombination
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta