Human T cell receptor occurrence patterns encode immune history, genetic background, and receptor specificity
- 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).
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Immunosequencing identifies signatures of cytomegalovirus exposure history and HLA-mediated effects on the T cell repertoirePublicly available in Adaptive Biotechnology's ImmuneAccess database.
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Dynamics of Individual T Cell Repertoires: From Cord Blood to CentenariansPublicly available in the NCBI's Short Read Archive with Bioproject accession PRJNA316572.
Article and author information
Author details
Frederick A Matsen
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.
Reviewing Editor
- Aleksandra M Walczak, École Normale Supérieure, France
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.
Version history
- Received: May 14, 2018
- Accepted: August 21, 2018
- Accepted Manuscript published: August 28, 2018 (version 1)
- 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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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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