Identifying immune signatures of common exposures through co-occurrence of T-cell receptors in tens of thousands of donors

Abstract

Memory T cells are records of clonal expansion from prior immune exposures, such as infections, vaccines and chronic diseases like cancer. A subset of the receptors of these expanded T cells in a typical immune repertoire are highly public, i.e., present in many individuals exposed to the same exposure. For the most part, the exposures associated with these public T cells are unknown. To identify public T-cell receptor signatures of immune exposures, we mined the immunosequencing repertoires of tens of thousands of donors to define clusters of co-occurring T cells. We first built co-occurrence clusters of T cells responding to antigens presented by the same Human Leukocyte Antigen (HLA) and then combined those clusters across HLAs. Each cross-HLA cluster putatively represents the public T-cell signature of a single prevalent exposure. Using repertoires from donors with known serological status for 7 prevalent exposures (HSV-1, HSV-2, EBV, Parvovirus, Toxoplasma gondii, Cytomegalovirus and SARS CoV-2), we identified a single T-cell cluster strongly associated with each exposure and used it to construct a highly sensitive and specific diagnostic model for the exposure. These T-cell clusters constitute the public immune responses to prevalent exposures, 7 known and many others unknown. By learning the exposure associations for more T cell clusters, this approach could be used to derive a ledger of a person's past and present immune exposures.

A Catalog of the Public T-cell Response to Cytomegalovirus

“…ECOclusters (Exposure Co-Occurrence clusters) are groups of up to tens of thousands of public T-cell receptor β chains (referred to here as “TCRs” and defined here as the combination of TCRβ V gene, J gene and CDR3 amino acid sequence) that tend to occur together in T-cell repertoires from tens of thousands of donors (May et al, 2024). Each ECOcluster putatively represents the component of the collective T-cell response to a prevalent exposure that is both “public” (i.e., shared among many people exposed to the exposure) and exposure-specific among those tens of thousands of donors.…”

“…The ECOcluster associated with cytomegalovirus (CMV) exposure (“the CMV ECOcluster”) comprises 26,106 TCRs (May et al, 2024). Higher repertoire breadth of the TCRs comprising the CMV ECOcluster (i.e., proportion of repertoire TCRs that are members of the CMV ECOcluster) is strongly associated with donor CMV seropositivity (one-sided Mann-Whitney U Test p =4.0e-66), and HLA-adjusted breadth defines a strong diagnostic classifier for CMV seropositivity in held-out donors (AUROC=0.96).…”