Biology subjects

Noakes, M. T.

Publications and source records attributed to Noakes, M. T..

2 recordsLinked to original sources

bioRxiv2026

HLA Alleles Imprint Distinct Biases in the Usage Preferences of TCR Vβ segments

T cells must co-recognize peptide and HLA, yet the extent to which this specificity is shaped by germline-encoded TCR-HLA contacts versus selection during thymic development has remained difficult to quantify. Leveraging population-scale TCR{beta} repertoires linked to donor HLA genotypes, we construct allele-specific V{beta} usage profiles and normalize them to repertoire-wide baselines to derive interpretable HLA-TCR V{beta} preference vectors. We demonstrate that different HLA alleles imprint distinct biases in the usage frequency of TCR V{beta} gene segments among the public TCRs that engage those alleles; consistent with germline-encoded TCR-HLA contact preferences, certain V{beta} genes are over-represented for particular HLA alleles. Similarities in HLA amino-acid sequence predict similarities in both their V{beta} preferences and peptide-binding motifs; a residue-level analysis disentangles HLA positions primarily associated with TCR engagement from those associated with peptide motifs. The TCR-associated HLA positions localize to canonical TCR-facing helices, whereas peptide-associated HLA positions track binding pockets, revealing distinct molecular routes by which HLA polymorphism shapes the TCR and peptide sides of recognition. CMV exposure stratifications confirmed these patterns are not explained by a few dominant infections. Together, these data support that germline-encoded constraints set the landscape of TCR-HLA compatibility, while thymic and peptide-driven forces tune the realized repertoire. These HLA-specific V{beta} biases are a biological prior that should provide a baseline for better understanding of TCR-pHLA specificity as a whole and should be accounted for in future evaluation of any TCR-pHLA specificity prediction methods.

immunology↗

bioRxiv2024

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

BackgroundMemory 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 {beta} sequences (TCRs) have known associations with exposures or specific peptides. MethodsWe 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. ResultsWe 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.

immunology↗