title: CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire.
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.
authors: The Emory Transplant Center, Emory University School of Medicine, Atlanta, GA;
authors: Yvonne
authors: Y
authors: Suessmuth
authors: 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;
authors: Rithun
authors: R
authors: Mukherjee
authors: Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA;
authors: Benjamin
authors: B
authors: Watkins
authors: Winship Cancer Institute of Emory University, Atlanta, GA;
authors: Divya T
authors: DT
authors: Koura
authors: Adaptive Biotechnologies Corporation, Seattle, WA;
authors: Knut
authors: K
authors: Finstermeier
authors: Adaptive Biotechnologies Corporation, Seattle, WA;
authors: Cindy
authors: C
authors: Desmarais
authors: The Emory Transplant Center, Emory University School of Medicine, Atlanta, GA;
authors: Linda
authors: L
authors: Stempora
authors: Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA;
authors: John T
authors: JT
authors: Horan
authors: Winship Cancer Institute of Emory University, Atlanta, GA;
authors: Amelia
authors: A
authors: Langston
authors: Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA;
authors: Muna
authors: M
authors: Qayed
authors: Winship Cancer Institute of Emory University, Atlanta, GA;
authors: Hanna J
authors: HJ
authors: Khoury
authors: Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA;
authors: Audrey
authors: A
authors: Grizzle
authors: The Emory Transplant Center, Emory University School of Medicine, Atlanta, GA;
authors: Jennifer A
authors: JA
authors: Cheeseman
authors: The Emory Transplant Center, Emory University School of Medicine, Atlanta, GA;
authors: Jason A
authors: JA
authors: Conger
authors: The Emory Transplant Center, Emory University School of Medicine, Atlanta, GA;
authors: Jennifer
authors: J
authors: Robertson
authors: Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA;
authors: Aneesah
authors: A
authors: Garrett
authors: The Emory Transplant Center, Emory University School of Medicine, Atlanta, GA;
authors: Allan D
authors: AD
authors: Kirk
authors: Winship Cancer Institute of Emory University, Atlanta, GA;
authors: Edmund K
authors: EK
authors: Waller
authors: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota School of Medicine, Minneapolis, MN; and.
authors: Bruce R
authors: BR
authors: Blazar
authors: The Emory Transplant Center, Emory University School of Medicine, Atlanta, GA;
authors: Aneesh K
authors: AK
authors: Mehta
authors: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA;
authors: Harlan S
authors: HS
authors: Robins
authors: 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.
authors: Leslie S
authors: LS
authors: Kean
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002648:Child; D003587:Cytomegalovirus / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D014184:Transplantation, Homologous; D014775:Virus Activation / Q000276:immunology*; D055815:Young Adult
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta