title: γδT cells elicited by CMV reactivation after allo-SCT cross-recognize CMV and leukemia.
abstract: Human cytomegalovirus (CMV) infections and relapse of disease remain major problems after allogeneic stem cell transplantation (allo-SCT), in particular in combination with CMV-negative donors or cordblood transplantations. Recent data suggest a paradoxical association between CMV reactivation after allo-SCT and reduced leukemic relapse. Given the potential of Vδ2-negative γδT cells to recognize CMV-infected cells and tumor cells, the molecular biology of distinct γδT-cell subsets expanding during CMV reactivation after allo-SCT was investigated. Vδ2(neg) γδT-cell expansions after CMV reactivation were observed not only with conventional but also cordblood donors. Expanded γδT cells were capable of recognizing both CMV-infected cells and primary leukemic blasts. CMV and leukemia reactivity were restricted to the same clonal population, whereas other Vδ2(neg) T cells interact with dendritic cells (DCs). Cloned Vδ1 T-cell receptors (TCRs) mediated leukemia reactivity and DC interactions, but surprisingly not CMV reactivity. Interestingly, CD8αα expression appeared to be a signature of γδT cells after CMV exposure. However, functionally, CD8αα was primarily important in combination with selected leukemia-reactive Vδ1 TCRs, demonstrating for the first time a co-stimulatory role of CD8αα for distinct γδTCRs. Based on these observations, we advocate the exploration of adoptive transfer of unmodified Vδ2(neg) γδT cells after allo-SCT to tackle CMV reactivation and residual leukemic blasts, as well as application of leukemia-reactive Vδ1 TCR-engineered T cells as alternative therapeutic tools.
authors.affiliation: Department of Hematology and Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: Scheper
authors.forename: S
authors.initials: S
authors.lastname: van Dorp
authors.forename: S
authors.initials: S
authors.lastname: Kersting
authors.forename: F
authors.initials: F
authors.lastname: Pietersma
authors.forename: C
authors.initials: C
authors.lastname: Lindemans
authors.forename: S
authors.initials: S
authors.lastname: Hol
authors.forename: S
authors.initials: S
authors.lastname: Heijhuurs
authors.forename: Z
authors.initials: Z
authors.lastname: Sebestyen
authors.forename: C
authors.initials: C
authors.lastname: Gründer
authors.forename: V
authors.initials: V
authors.lastname: Marcu-Malina
authors.forename: A
authors.initials: A
authors.lastname: Marchant
authors.forename: C
authors.initials: C
authors.lastname: Donner
authors.forename: B
authors.initials: B
authors.lastname: Plachter
authors.forename: D
authors.initials: D
authors.lastname: Vermijlen
authors.forename: D
authors.initials: D
authors.lastname: van Baarle
authors.forename: J
authors.initials: J
authors.lastname: Kuball
mesh_terms: D003587:Cytomegalovirus / Q000502:physiology*; D006801:Humans; D007938:Leukemia / Q000276:immunology / Q000601:surgery*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D033581:Stem Cell Transplantation; D016176:T-Lymphocyte Subsets; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous; D014775:Virus Activation
chemical_list: D016692:Receptors, Antigen, T-Cell, gamma-delta