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Blood. 2015 Jun 18;125(25):3835-50. doi: 10.1182/blood-2015-03-631853. Epub 2015 Apr 7.

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

Author information

1
The Emory Transplant Center, Emory University School of Medicine, Atlanta, GA;
2
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle WA;
3
Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA;
4
Winship Cancer Institute of Emory University, Atlanta, GA;
5
Adaptive Biotechnologies Corporation, Seattle, WA;
6
Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota School of Medicine, Minneapolis, MN; and.
7
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA;
8
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle WA; Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA; Department of Pediatrics, University of Washington, Seattle, WA.

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 B(high)/CD28(low)/CD57(high)/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.

PMID:
25852054
PMCID:
PMC4473113
DOI:
10.1182/blood-2015-03-631853
[Indexed for MEDLINE]
Free PMC Article

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