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

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.

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Figure 1: Experimental and analytical overview.
Figure 2: Identification of CMV-associated TCRβs.
Figure 3: The incidence of CMV-associated TCRβs is diagnostic of CMV serostatus.
Figure 4: Identification of HLA-allele-associated TCRβs.

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Acknowledgements

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

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Ryan O Emerson.

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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.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 (PDF 644 kb)

Supplementary Table 1

Detailed demographic and phenotypic information for subjects in Cohorts 1 and 2. (XLSX 58 kb)

Supplementary Table 2

List of the 164 CMV-associated TCRβs. (XLSX 59 kb)

Supplementary Table 3

List of 1054 previously published CMV-reactive TCRβs. (XLSX 107 kb)

Supplementary Table 4

Overlap between CMV-associated TCRβs and previously published, TCR-reactive TCRβs (XLSX 14 kb)

Supplementary Table 5

List of antigens used in the MIRA experiment. (XLSX 29 kb)

Supplementary Table 6

Result of the MIRA experiment. (XLSX 43 kb)

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Emerson, R., DeWitt, W., Vignali, M. et al. Immunosequencing identifies signatures of cytomegalovirus exposure history and HLA-mediated effects on the T cell repertoire. Nat Genet 49, 659–665 (2017). https://doi.org/10.1038/ng.3822

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