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CMV reactivation drives post-transplant 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. Mehta, Harlan S. Robins and Leslie S. Kean

Key points

  • CMV reactivation fundamentally resets post-transplant CD8 reconstitution, resulting in massive expansion of CMV-specific CD8 Tem.

  • CMV reactivation is associated with defects in the underlying TCRβ immune repertoire.

Abstract

Although CMV reactivation has long been implicated in post-transplant 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 HSCT. We observed that CMV reactivation drove a >50-fold specific expansion of Granzyme Bhigh/CD28low/CD57high/CD8+ effector-memory T cells and resulted in a linked contraction of all naïve T cells, including CD31+/CD4+ putative thymic emigrants. 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. Registered to www.Clinicaltrials.gov as #NCT01012492.

  • Submitted March 2, 2015.
  • Accepted March 26, 2015.