Immunosequencing identifies signatures of cytomegalovirus exposure history and HLA-mediated effects on the T-cell repertoire

An individual's T-cell repertoire dynamically encodes their pathogen exposure history. To determine if specific pathogen exposure signatures can be identified by documenting public TCRs, we profiled the T-cell repertoire of 666 subjects with known cytomegalovirus (CMV) serostatus by immunosequencing, and we developed a statistical classification framework that can diagnose CMV status from the resulting catalog of TCRb sequences with high specificity and sensitivity, both in the original cohort and in an independent validation cohort of 120 subjects. We confirmed that 3 of the identified CMV-associated TCRb bind CMV in vitro, and furthermore we used this approach to accurately predict the HLA-A and -B alleles of most subjects in the first cohort. Since all memory T-cell responses are encoded in the common format of somatic TCR recombination, our approach could potentially be generalized to a wide variety of disease states, as well as other immunological phenotypes as a highly parallelizable diagnostic strategy.