Local and Global Variability in Developing Human T-Cell Repertoires

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Abstract
The adaptive immune response relies on T cells that combine phenotypic specialization with diversity of T-cell receptors (TCRs) to recognize a wide range of pathogens. TCRs are acquired and selected during T-cell maturation in the thymus. Characterizing TCR repertoires across individuals and T-cell maturation stages is important for better understanding adaptive immune responses and for developing new diagnostics and therapies. Analyzing a dataset of human TCR repertoires from thymocyte subsets, we find that the variability between individuals generated during the TCR V(D)J recombination is maintained through all stages of T-cell maturation and differentiation. The interindividual variability of repertoires of the same cell type is of comparable magnitude to the variability across cell types within the same individual. To zoom in on smaller scales than whole repertoires, we defined a distance measuring the relative overlap of locally similar sequences in repertoires. We find that the whole repertoire models correctly predict local similarity networks, suggesting a lack of forbidden T-cell receptor sequences. The local measure correlates well with distances calculated using whole repertoire traits and carries information about cell types. Published by the American Physical Society 2024
Funding Information
  • H2020 European Research Council (COG 724208, 322856)
  • Agence Nationale de la Recherche (ANR-19-CE45-0018, ANR-16-RHUS-0001, ANR-11-IDEX-0004-02)
  • Deutsche Forschungsgemeinschaft
  • National Institutes of Health (GM142795)
  • National Science Foundation (2045054)
  • European Research Area Network on Cardiovascular Diseases (ANR-18-ECVD-0001)
  • University of Washington
  • H2020 European Research Council (COG 724208, 322856)
  • Agence Nationale de la Recherche (ANR-19-CE45-0018, ANR-16-RHUS-0001, ANR-11-IDEX-0004-02)
  • Deutsche Forschungsgemeinschaft
  • National Institutes of Health (GM142795)
  • National Science Foundation (2045054)
  • European Research Area Network on Cardiovascular Diseases (ANR-18-ECVD-0001)
  • University of Washington

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