Immune signatures of common exposures through co-occurrence of T-cell receptors in tens of thousands of donors
- 1Adaptive Biotechnologies, Seattle, WA, USA
- 2Microsoft Research, Redmond, WA, USA
Abstract
Background Memory T cells are records of clonal expansion from prior immune exposures such as infections, vaccines and chronic diseases. Some of the receptors of these expanded T cell clones in a typical immune repertoire are highly public (present in many individuals) because they respond to the same peptide from a prevalent immune exposure, presented by the same Human Leukocyte Antigen (HLA) allele. Only a tiny fraction of public T-cell receptor β sequences (TCRs) have known associations with exposures or specific peptides. Methods We mined the TCR repertoires of tens of thousands of donors to define “ECOclusters”: clusters of public TCRs that tend to occur in the same donors. First, we built models to infer donor HLA type from the TCR repertoire, then associated public TCRs with HLA alleles. Next, we derived co-occurrence clusters of TCRs responding to antigens presented by the same HLA allele, then combined those clusters by co-occurrence across HLA alleles. Each such cross-HLA ECOcluster putatively represents a public TCR signature of a single exposure. Results We constructed sensitive, specific models to predict the presence of 220 HLA alleles from TCR repertoires and clustered 8,618,285 HLA allele-associated TCRs to define 11,058 ECOclusters. Using serologically labeled repertoires, we identified ECOclusters associated with HSV-1, HSV-2, EBV, Parvovirus, Toxoplasma gondii , Cytomegalovirus and SARS-CoV-2, and constructed sensitive, specific classifiers of exposure. ECOclusters represent a step toward deciphering the ledger of immune exposure history encoded by the T-cell repertoire.
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BibTeX
@article{may2026immune,
title = {{Immune signatures of common exposures through co-occurrence of T-cell receptors in tens of thousands of donors}},
author = {Damon May and Steven Woodhouse and Matthew T. Noakes and KATHRYN DOROSCHAK and Rebecca Elyanow and Amanda J. Moore and Edward J. Osborne and Brad Greenfield and Tim Hayes and Ruth T. Taniguchi and Zheng Yang and John Grino and Rachel Byron and Jamie Oaks and Haiyin Chen‐Harris and Anna Sherwood and Julia Greissl and Bryan Howie and Mark Klinger and Harlan S. Robins},
journal = {Frontiers in Immunology},
year = {2026},
month = sep,
doi = {10.3389/fimmu.2026.1944643},
url = {https://doi.org/10.3389/fimmu.2026.1944643},
note = {CC BY},
}
RIS
TY - JOUR
TI - Immune signatures of common exposures through co-occurrence of T-cell receptors in tens of thousands of donors
AU - Damon May
AU - Steven Woodhouse
AU - Matthew T. Noakes
AU - KATHRYN DOROSCHAK
AU - Rebecca Elyanow
AU - Amanda J. Moore
AU - Edward J. Osborne
AU - Brad Greenfield
AU - Tim Hayes
AU - Ruth T. Taniguchi
AU - Zheng Yang
AU - John Grino
AU - Rachel Byron
AU - Jamie Oaks
AU - Haiyin Chen‐Harris
AU - Anna Sherwood
AU - Julia Greissl
AU - Bryan Howie
AU - Mark Klinger
AU - Harlan S. Robins
PY - 2026
DA - 2026/09/18
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1944643
UR - https://doi.org/10.3389/fimmu.2026.1944643
AB - Background Memory T cells are records of clonal expansion from prior immune exposures such as infections, vaccines and chronic diseases. Some of the receptors of these expanded T cell clones in a typical immune repertoire are highly public (present in many individuals) because they respond to the same peptide from a prevalent immune exposure, presented by the same Human Leukocyte Antigen (HLA) allele. Only a tiny fraction of public T-cell receptor β sequences (TCRs) have known associations with exposures or specific peptides. Methods We mined the TCR repertoires of tens of thousands of donors to define “ECOclusters”: clusters of public TCRs that tend to occur in the same donors. First, we built models to infer donor HLA type from the TCR repertoire, then associated public TCRs with HLA alleles. Next, we derived co-occurrence clusters of TCRs responding to antigens presented by the same HLA allele, then combined those clusters by co-occurrence across HLA alleles. Each such cross-HLA ECOcluster putatively represents a public TCR signature of a single exposure. Results We constructed sensitive, specific models to predict the presence of 220 HLA alleles from TCR repertoires and clustered 8,618,285 HLA allele-associated TCRs to define 11,058 ECOclusters. Using serologically labeled repertoires, we identified ECOclusters associated with HSV-1, HSV-2, EBV, Parvovirus, Toxoplasma gondii , Cytomegalovirus and SARS-CoV-2, and constructed sensitive, specific classifiers of exposure. ECOclusters represent a step toward deciphering the ledger of immune exposure history encoded by the T-cell repertoire.
SN - 1664-3224
ER -