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 highresolution 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. 6

Longitudinal high-throughput TCR repertoire profiling reveals the dynamics of T cell memory formation after mild COVID-19 infection

“…Using sets of HLA-associated TCRbeta sequences from ref. [31], we build a simple classifier to predict the HLA alleles of donors from both the control and COVID-19 cohorts exploiting the presence of TCRbeta sequences associated with certain HLA alleles. We found that the CD4+ TCRbeta motif from donor W occurs preferentially in donors predicted to have DRB1*07:01 allele, while the motif from donor M appears to be HLA-DRB1*03:01-restricted.…”

“…Computational prediction of HLA-types. To predict HLA-types from TCR repertoires we used sets of HLA-associated TCR sequences from [31]. We use TCRbeta repertoires of 666 donors from cohort from [29], for which HLA-typing information is available in ref.…”

T‐cell receptor diversity as a prognostic biomarker in melanoma patients

“…Immunosequencing of the TCR allows the specification and the quantification of each T‐cell clone within a sample, providing information on immune responsiveness. The diverse TCR repertoire thus dynamically encodes immune exposure history (DeWitt et al, ). The diversity comprises both richness, that measures the number of different specificities in the sample (number of T‐cell clones with unique TCRs), and evenness, that measures the relative abundance of the different specificities.…”

The expanding role of systems immunology in decoding the T cell receptor repertoire

“…Still, a recent study utilizing a large data set of bulk TCRβ sequences showed the ability to identify strong associations between single chains and CMV infection status [71]. A follow up report analyzing the same data set with a clustering method expanded these findings and indicated that the specificity of a surprisingly significant portion of the peripheral repertoire can be accounted for in some individuals [72]. Another recent study has used the same data set to demonstrate an approach to identify public antigen-specific TCR sequences using a recombination model to consider the two major mechanisms of convergent recombination and convergent selection for the inter-individual sharing of TCR sequences [73].…”