T-cell receptor repertoires share a restricted set of public and abundant CDR3 sequences that are associated with self-related immunity

  1. Nir Friedman1
  1. 1Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel;
  2. 2Division of Infection and Immunity, The Cruciform Building, UCL, London WC1 6BT, United Kingdom
  1. Corresponding authors: irun.cohen{at}weizmann.ac.il, nir.friedman{at}weizmann.ac.il
  1. 3 These authors contributed equally to this work.

  • 4 Present address: African Institute for Mathematical Sciences, Muizenberg 7945, South Africa

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.

Footnotes

  • Received December 6, 2013.
  • Accepted July 8, 2014.

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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