Characterization of High-Avidity Cytomegalovirus-Specific T Cells with Differential Tetramer Binding Coappearing after Allogeneic Stem Cell Transplantation

Research output: Contribution to journalArticle

Authors

  • Justyna Ogonek
  • Christian Schultze-Florey
  • Pavankumar Varanasi
  • Susanne Luther
  • Patrick Schweier
  • Wolfgang Kühnau
  • Gudrun Göhring
  • Elke Dammann
  • Michael Stadler
  • Arnold Ganser
  • Ulrike Koehl
  • Christian Koenecke
  • Eva M Weissinger
  • Lothar Hambach

Colleges, School and Institutes

External organisations

  • Laboratory of Transplantation Biology, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover 30625, Germany.
  • Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover 30625, Germany.
  • Institute of Immunology, Hannover Medical School, Hannover 30625, Germany.
  • German Center for Infection Research, Hannover 30625, Germany.
  • Institute for Human Genetics, Hannover Medical School, Hannover 30625, Germany; and.
  • Institute of Cellular Therapeutics, Hannover Medical School, Hannover 30625, Germany.
  • Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover 30625, Germany; hambach.lothar@mh-hannover.de.

Abstract

CMV reactivation is a major complication after allogeneic stem cell transplantation (SCT). Immune reconstitution of CMV-specific CTLs (CMV-CTLs) is essential for virus control. During CMV-CTL monitoring using mutated HLA/CMV tetramers selectively detecting high-avidity T cells, we observed coappearance of CMV-CTLs with low (CMV tetlow CTLs) and high tetramer binding (CMV tethigh CTLs) in 53/115 CMV IgG+ patients stem cell transplanted from CMV IgG+ donors. However, the relevance of these coappearing differentially tetramer binding ("dual") CMV-CTLs was unclear. In this study, we investigated the kinetics, properties, and clinical impact of coappearing CMV tetlow and tethigh CTLs after allogeneic SCT. Patients with dual CMV-CTLs had more CMV tethigh than tetlow CTLs. Chimerism analysis of isolated CMV tetlow and tethigh CTLs revealed their exclusive donor origin. CMV tetlow and tethigh CTLs had an identical effector memory CD45RA-CCR7- and CD45RA+CCR7- T cell distribution, equal differentiation, senescence, and exhaustion marker expression and were negative for regulatory CD8+ T cell markers. Isolated CMV tetlow and tethigh CTLs were equally sensitive to CMV peptides in IFN-γ release and cytotoxicity assays. However, CMV tethigh CTLs proliferated more in response to low CMV peptide concentrations than tetlow CTLs. TCR repertoire analysis revealed that CMV tetlow and tethigh CTLs use different TCRs. Finally, dual CMV-CTLs were not associated with CMV antigenemia. In conclusion, these data show for the first time, to our knowledge, that both CMV tetlow and tethigh CTLs are functional effector T cells differing by proliferation, numbers in peripheral blood, and probably by their precursors without increasing the CMV reactivation risk after allogeneic SCT.

Details

Original languageEnglish
Pages (from-to)792-805
Number of pages14
JournalJournal of Immunology
Volume199
Issue number2
Publication statusPublished - 15 Jul 2017

Keywords

  • Adolescent, Adult, Aged, CD3 Complex/genetics, Cell Proliferation, Cytomegalovirus/chemistry, Cytomegalovirus Infections/immunology, Female, HLA Antigens/immunology, Hematopoietic Stem Cell Transplantation, Humans, Interferon-gamma/immunology, Kinetics, Leukocyte Common Antigens/genetics, Male, Middle Aged, Receptors, CCR7/deficiency, Stem Cell Transplantation, T-Lymphocytes, Cytotoxic/immunology, Tissue Donors, Transplantation, Homologous, Young Adult