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

Nat Genet. 2017 May;49(5):659-665. doi: 10.1038/ng.3822. Epub 2017 Apr 3.

Abstract

An individual's T cell repertoire dynamically encodes their pathogen exposure history. To determine whether pathogen exposure signatures can be identified by documenting public T cell receptors (TCRs), we profiled the T cell repertoire of 666 subjects with known cytomegalovirus (CMV) serostatus by immunosequencing. We developed a statistical classification framework that could diagnose CMV status from the resulting catalog of TCRβ sequences with high specificity and sensitivity in both the original cohort and a validation cohort of 120 different subjects. We also confirmed that three of the identified CMV-associated TCRβ molecules bind CMV in vitro, and, moreover, we used this approach to accurately predict the HLA-A and HLA-B alleles of most subjects in the first cohort. As 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.

MeSH terms

  • Algorithms
  • Cohort Studies
  • Cytomegalovirus / genetics
  • Cytomegalovirus / immunology*
  • Cytomegalovirus / physiology
  • Epitopes, T-Lymphocyte / genetics
  • Epitopes, T-Lymphocyte / immunology
  • HLA Antigens / genetics
  • HLA Antigens / immunology*
  • HLA-A Antigens / genetics
  • HLA-A Antigens / immunology
  • HLA-B Antigens / genetics
  • HLA-B Antigens / immunology
  • High-Throughput Nucleotide Sequencing / methods*
  • Histocompatibility Testing / methods
  • Host-Pathogen Interactions / immunology
  • Humans
  • Models, Immunological
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • Reproducibility of Results
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / virology

Substances

  • Epitopes, T-Lymphocyte
  • HLA Antigens
  • HLA-A Antigens
  • HLA-B Antigens
  • Receptors, Antigen, T-Cell