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

Nature Genetics volume 49, pages 659665 (2017) | Download Citation


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.

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The authors would like to thank M. Chung and other technical staff in the Adaptive Biotechnologies immunosequencing laboratory for their work on this project, S. House for helping compile the list of CMV-reactive TCRβ sequences from the literature, and C. Linkem and K. Boland for assistance with sample tagging for the immuneACCESS project. This work was funded in part by an award from the W.M. Keck Foundation Medical Research Program to H.S.R. and C.S.C.

Author information

Author notes

    • Ryan O Emerson
    •  & William S DeWitt

    These authors contributed equally to this work.

    • Mark Rieder
    •  & Harlan S Robins

    These authors jointly directed this work.


  1. Adaptive Biotechnologies, Seattle, Washington, USA.

    • Ryan O Emerson
    • , William S DeWitt
    • , Marissa Vignali
    • , Joyce K Hu
    • , Edward J Osborne
    • , Cindy Desmarais
    • , Mark Klinger
    • , Mark Rieder
    •  & Harlan S Robins
  2. Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • William S DeWitt
    •  & Harlan S Robins
  3. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Jenna Gravley
    • , Christopher S Carlson
    •  & John A Hansen


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J.G. and J.A.H. obtained the DNA samples and determined the CMV status and HLA type of the subjects. R.O.E., C.S.C., M.R., and H.S.R. conceived and designed the experiments. M.R. generated the sequence data. R.O.E., W.S.D., M.V., and C.D. analyzed the results. R.O.E. and W.S.D. performed the statistical analyses. M.V. and C.D. performed the literature searches of CMV-specific TCRs. J.K.H., E.J.O., and M.K. performed and analyzed in vitro confirmation experiments. R.O.E., W.S.D., M.V., M.K., and H.S.R. wrote the manuscript.

Competing interests

H.S.R. has employment, equity ownership, patents, and royalties with Adaptive Biotechnologies, and C.S.C. has consultancy, equity ownership, patents, and royalties with Adaptive Biotechnologies; R.O.E., W.S.D., M.V., C.D., J.K.H., E.J.O., M.K., and M.R. have employment and equity ownership with Adaptive Biotechnologies.

Corresponding author

Correspondence to Ryan O Emerson.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–4

Excel files

  1. 1.

    Supplementary Table 1

    Detailed demographic and phenotypic information for subjects in Cohorts 1 and 2.

  2. 2.

    Supplementary Table 2

    List of the 164 CMV-associated TCRβs.

  3. 3.

    Supplementary Table 3

    List of 1054 previously published CMV-reactive TCRβs.

  4. 4.

    Supplementary Table 4

    Overlap between CMV-associated TCRβs and previously published, TCR-reactive TCRβs

  5. 5.

    Supplementary Table 5

    List of antigens used in the MIRA experiment.

  6. 6.

    Supplementary Table 6

    Result of the MIRA experiment.

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