De novo detection and HLA-association of public T cell responses to Cytomegalovirus using high-throughput immune repertoire sequencing (VIR1P.1134)

Abstract

Abstract We investigated the public T cell response to cytomegalovirus by sequencing rearranged T cell receptors (TCRs) in 640 subjects (287 with & 353 without CMV). We performed an experiment similar to a GWAS study, assessing the concordance of millions of unique TCRs with CMV serostatus, looking for significant associations. With CMV serostatus and TCR sequencing data, we identify 142 public T cell responses to CMV (each with p ≤ 1.0 x 10-4; FDR ≈ 0.20). Using this method to identify public clones, we predict CMV serostatus in a leave-one-out cross-validation experiment with a diagnostic odds ratio of 66. Using HLA typing, we then estimate the HLA-association of each public CMV clone by assessing the over-representation of particular HLA types in associated subjects. Of 142 CMV public clones, 26 were HLA-associated at p < 10-6; no clones were significantly associated with multiple HLA alleles. When comparing our results to the literature, we find substantial concordance; most previously-reported public CMV clones are seen in our data, though only 2 are significantly associated with CMV serostatus in this cohort; both were significantly HLA-associated and in both cases the associated allele confirms previous findings. We demonstrate the validity of association studies using immunosequencing for detection and HLA-association of public T cell responses to infection, and report that assessing the presence of public T cell responses can serve as a powerful diagnostic classifier.