title: CMV promotes recipient T-cell immunity following reduced-intensity T-cell-depleted HSCT, significantly modulating chimerism status.
abstract: Cytomegalovirus (CMV) remains a significant cause of morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). Clinical risk varies according to a number of factors, including recipient/donor CMV serostatus. Current dogma suggests risk is greatest in seropositive recipient (R+)/seronegative donor (D-) transplants and is exacerbated by T-cell depletion. We hypothesized that in the setting of reduced-intensity T-cell-depleted conditioning, recipient-derived CMV-specific T cells escaping deletion may contribute significantly to CMV-specific immunity and might therefore also influence chimerism status. We evaluated 105 recipients of alemtuzumab-based reduced-intensity HSCT and collated details on CMV infection episodes and T-cell chimerism. We used CMV-specific HLA multimers to enumerate CMV-specific T-cell numbers and select cells to assess chimerism status in a subset of R+/D- and R+/seropositive donor patients. We show that in R+/D- patients, CMV-specific T cells are exclusively of recipient origin, can protect against recurrent CMV infections, and significantly influence the chimerism status toward recipients. The major findings were replicated in a separate validation cohort. T-cell depletion in the R+/D- setting may actually, therefore, foster more rapid reconstitution of protective antiviral immunity by reducing graft-vs-host directed alloreactivity and the associated elimination of the recipient T-cell compartment. Finally, conversion to donor chimerism after donor lymphocytes is associated with clinically occult transition to donor-derived immunity.
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom; Department of Haematology, University College London Hospital, London, United Kingdom; and.
authors.forename: Rob S
authors.initials: RS
authors.lastname: Sellar
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom;
authors.forename: Frederick Arce
authors.initials: FA
authors.lastname: Vargas
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom;
authors.forename: Jake Y
authors.initials: JY
authors.lastname: Henry
authors.affiliation: Department of Haematology, Royal Free Hospital, London, United Kingdom.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Verfuerth
authors.affiliation: Department of Haematology, University College London Hospital, London, United Kingdom; and.
authors.forename: Sarah
authors.initials: S
authors.lastname: Charrot
authors.affiliation: Department of Haematology, Royal Free Hospital, London, United Kingdom.
authors.forename: Brendan
authors.initials: B
authors.lastname: Beaton
authors.affiliation: Department of Haematology, Royal Free Hospital, London, United Kingdom.
authors.forename: Ronjon
authors.initials: R
authors.lastname: Chakraverty
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom;
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Quezada
authors.affiliation: Department of Haematology, Royal Free Hospital, London, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Mackinnon
authors.affiliation: Department of Haematology, University College London Hospital, London, United Kingdom; and.
authors.forename: Kirsty J
authors.initials: KJ
authors.lastname: Thomson
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom; Department of Haematology, University College London Hospital, London, United Kingdom; and.
authors.forename: Karl S
authors.initials: KS
authors.lastname: Peggs
mesh_terms: D064591:Allografts; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology*; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007111:Immunity, Cellular; D008212:Lymphocyte Depletion; D008297:Male; D018183:Transplantation Chimera / Q000276:immunology*