Human T cell receptor occurrence patterns encode immune history, genetic background, and receptor specificity

  1. William S DeWitt
  2. Anajane Smith
  3. Gary Schoch
  4. John A Hansen
  5. Frederick A Matsen
  6. Philip Bradley  Is a corresponding author
  1. Fred Hutchinson Cancer Research Center, United States

Abstract

The T cell receptor (TCR) repertoire encodes immune exposure history through the dynamic formation of immunological memory. Statistical analysis of repertoire sequencing data has the potential to decode disease associations from large cohorts with measured phenotypes. However, the repertoire perturbation induced by a given immunological challenge is conditioned on genetic background via major histocompatibility complex (MHC) polymorphism. We explore associations between MHC alleles, immune exposures, and shared TCRs in a large human cohort. Using a previously published repertoire sequencing dataset augmented with high-resolution MHC genotyping, our analysis reveals rich structure: striking imprints of common pathogens, clusters of co-occurring TCRs that may represent markers of shared immune exposures, and substantial variations in TCR-MHC association strength across MHC loci. Guided by atomic contacts in solved TCR:peptide-MHC structures, we identify sequence covariation between TCR and MHC. These insights and our analysis framework lay the groundwork for further explorations into TCR diversity.

Data availability

Data and analysis scripts needed to reproduce the findings of this study have been deposited in the Zenodo database (doi:10.5281/zenodo.1248193).

The following previously published data sets were used

Article and author information

Author details

  1. William S DeWitt

    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6802-9139
  2. Anajane Smith

    Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Gary Schoch

    Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. John A Hansen

    Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Frederick A Matsen

    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0607-6025
  6. Philip Bradley

    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    For correspondence
    pbradley@fredhutch.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0224-6464

Funding

National Institutes of Health (CA015704)

  • Anajane Smith
  • Gary Schoch
  • John A Hansen
  • Frederick A Matsen
  • Philip Bradley

Fred Hutchinson Cancer Research Center (Salary support)

  • Philip Bradley

National Institutes of Health (R01-HL105914)

  • Anajane Smith
  • Gary Schoch
  • John A Hansen

National Institutes of Health (R01-GM113246)

  • Frederick A Matsen

National Institutes of Health (U19-AI117891)

  • Frederick A Matsen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: All samples were collected and analyzed, and informed consent and consent to publish were obtained, according to research protocols approved by the Fred Hutchinson Cancer Research Center (FHCRC) Institutional Review Board.

Reviewing Editor

  1. Aleksandra M Walczak, École Normale Supérieure, France

Publication history

  1. Received: May 14, 2018
  2. Accepted: August 21, 2018
  3. Accepted Manuscript published: August 28, 2018 (version 1)
  4. Version of Record published: September 28, 2018 (version 2)

Copyright

© 2018, DeWitt et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. William S DeWitt
  2. Anajane Smith
  3. Gary Schoch
  4. John A Hansen
  5. Frederick A Matsen
  6. Philip Bradley
(2018)
Human T cell receptor occurrence patterns encode immune history, genetic background, and receptor specificity
eLife 7:e38358.
https://doi.org/10.7554/eLife.38358

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