CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire

Yvonne Suessmuth, Rithun Mukherjee, Benjamin Watkins, Divya T. Koura, Knut Finstermeier, Cindy Desmarais, Linda Stempora, John T. Horan, Amelia Langston, Muna Qayed, Hanna J. Khoury, Audrey Grizzle, Jennifer A. Cheeseman, Jason A. Conger, Jennifer Robertson, Aneesah Garrett, Allan D. Kirk, Edmund K. Waller, Bruce R. Blazar, Aneesh K. MehtaHarlan S. Robins, Leslie S. Kean

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

Although cytomegalovirus (CMV) reactivation has long been implicated in posttransplant immune dysfunction, the molecular mechanisms that drive this phenomenon remain undetermined. To address this, we combined multiparameter flow cytometric analysis and T-cell subpopulation sorting with high-throughput sequencing of the T-cell repertoire, to produce a thorough evaluation of the impact of CMV reactivation on T-cell reconstitution after unrelated-donor hematopoietic stem cell transplant. We observed that CMV reactivation drove a >50-fold specific expansion of Granzyme Bhigh/CD28low/CD57high/CD8+ effector memory T cells (Tem) and resulted in a linked contraction of all naive T cells, including CD31+/CD4+ putative thymic emigrants. T-cell receptor β (TCRβ) deep sequencing revealed a striking contraction of CD8+ Tem diversity due to CMV-specific clonal expansions in reactivating patients. In addition to querying the topography of the expanding CMV-specific T-cell clones, deep sequencing allowed us, for the first time, to exhaustively evaluate the underlying TCR repertoire. Our results reveal new evidence for significant defects in the underlying CD8 Tem TCR repertoire in patients who reactivate CMV, providing the first molecular evidence that, in addition to driving expansion of virus-specific cells, CMV reactivation has a detrimental impact on the integrity and heterogeneity of the rest of the T-cell repertoire. This trial was registered at www.clinicaltrials. gov as #NCT01012492.

Original languageEnglish (US)
Pages (from-to)3835-3850
Number of pages16
JournalBlood
Volume125
Issue number25
DOIs
StatePublished - Jun 18 2015

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    Suessmuth, Y., Mukherjee, R., Watkins, B., Koura, D. T., Finstermeier, K., Desmarais, C., Stempora, L., Horan, J. T., Langston, A., Qayed, M., Khoury, H. J., Grizzle, A., Cheeseman, J. A., Conger, J. A., Robertson, J., Garrett, A., Kirk, A. D., Waller, E. K., Blazar, B. R., ... Kean, L. S. (2015). CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire. Blood, 125(25), 3835-3850. https://doi.org/10.1182/blood-2015-03-631853