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Prepublished online as a Blood First Edition Paper on May 1, 2003; DOI 10.1182/blood-2002-11-3407.
Submitted November 8, 2002
Accepted April 14, 2003
Retrovirus-mediated gene transfer in polyclonal T cells results in lower apoptosis and enhanced ex vivo cell expansion of CMV-reactive CD8 T cells as compared to EBV-reactive CD8 T cells
Delphine Sauce, Nathalie Rufer, Patricia Mercier, Marie Bodinier, Jean-Paul Remy-Martin, Anne Duperrier, Christophe Ferrand, Patrick Herve, Pedro Romero, Francois Lang, Pierre Tiberghien, and Eric Robinet*
INSERM E-0119, UPRES EA-2284, EFS Bourgogne Franche-Comte, Besancon, France
NCCR Molecular Oncology, Swiss Institute for Cancer Research, Epalinges, Switzerland
INSERM, Unite 463, Institut de Biologie, Nantes, France
Multidisciplinary Oncology Center, University Hospital, Lausanne, Switzerland
* Corresponding author; email: eric.robinet{at}efs.sante.fr.
To modulate alloreactivity after hematopoietic stem cell transplantation, "suicide" gene-modified donor T cells (GMC) have been administered with an allogeneic T-cell-depleted marrow graft. We previously demonstrated that such GMC, generated after CD3 activation, retrovirus-mediated transduction and G418-selection, had an impaired Epstein-Barr Virus (EBV) reactivity, likely to result in an altered control of EBV-induced lymphoproliferative disease. To further characterize the anti-viral potential of GMC, we compared the frequencies of cytomegalovirus (CMV)- specific CD8+ T (CMV-T) cells and EBV-specific CD8+ T cells (EBV-T) within GMC from CMV- and EBV-double seropositive donors. Unlike anti-EBV responses, the anti-CMV responses were not altered by GMC preparation. During the first days of culture, CMV-T cells exhibited a lower level of CD3-induced apoptosis than did EBV-T cells. In addition, the CMV-T cells escaping initial apoptosis subsequently underwent a higher expansion rate than EBV-T cells. The differential early sensitivity to apoptosis could be in relation with the "recent activation" phenotype of EBV-T cells as evidenced by a higher level of CD69 expression. Furthermore, EBV-T cells were found to have a CD45RA- CD27+ CCR7- effector memory phenotype while CMV-T cells had a CD45RA+ CD27- CCR7- terminal effector phenotype. Such differences could be contributive, since bulk CD8+ CD27- cells had a higher expansion than did bulk CD8+ CD27+ cells. Overall, ex vivo T-cell culture differentially affects apoptosis, long-term proliferation and overall survival of CMV-T and EBV-T cells. Such functional differences need to be taken into account when designing cell and/or gene therapy protocols involving ex vivo T-cell manipulation.
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