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

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.

T‐cell receptor and B‐cell receptor repertoire profiling in adaptive immunity

“… by Dewitt et al . identified clusters of TCRs that co‐occur with certain MHC‐alleles, many of which contained previously identified TCRs specific to common pathogens. Second, for some epitopes there might be few or no public sequences .…”

“…First, for TCRs, sharing depends on the recognition of the same epitope, where the implication is that the antigen is presented by the same or highly similar MHC-alleles. A reanalysis of the abovementioned data from Emerson et al [88] by Dewitt et al [97] identified clusters of TCRs that co-occur with certain MHC-alleles, many of which contained previously identified TCRs specific to common pathogens. Second, for some epitopes there might be few or no public sequences [98].…”

Pre‐existing heterologous T‐cell immunity and neoantigen immunogenicity

“…Consistent with the frequent exposure to common viral pathogens, such as human cytomegalovirus, human papillomavirus and hepatitis C virus, in humans, epitopes from these viruses were found to cross‐react with neoantigens in cancer patients (Table ). Interestingly, the frequencies of TCR repertoire recognising these common pathogens are higher because of the clonal expansion . Thus, it is most likely that the neoantigens that cross‐react with antigens of common pathogens elicit more robust T‐cell response as a result of recalling heterologous memory response than those neoantigens that are recognised by naïve T cells.…”

“…Interestingly, the frequencies of TCR repertoire recognising these common pathogens are higher because of the clonal expansion. 61 Thus, it is most likely that the neoantigens that cross-react with antigens of common pathogens elicit more robust T-cell response as a result of recalling heterologous memory response than those neoantigens that are recognised by na€ ıve T cells.…”

A framework for annotation of antigen specificities in high-throughput T-cell repertoire sequencing studies

“…Existing computational methods for TCR repertoire annotation allow both matching against a database of known antigen specificities [12], [13] and clustering of TCR sequences for de novo motif detection [4], [14]. Annotation of a large number of TCR repertoires from healthy donors [15], [16] demonstrates both high variance of frequencies of epitope-specific T-cells and the imprint of past and ongoing pathogen encounters. Thus, de novo discovery of Tcells associated with antigens of interest or certain disease appears to be a hard problem, complicated by the biases in the structure of the naive (unperturbed) TCR repertoire [17], presence of existing clonal expansions specific to unrelated pathogens and high number of false positives that result from the extremely high diversity of the TCR repertoire.…”