Submitted November 28, 2006
Accepted April 25, 2007
The immune response to lentiviral-delivered transgene is modulated in vivo by transgene expressing antigen presenting cells but not by CD4+CD25+ regulatory T cells
Andrea Annoni, Manuela Battaglia, Antonia Follenzi, Angelo Lombardo, Lucia Sergi-Sergi, Luigi Naldini, and Maria-Grazia Roncarolo*
San Raffaele Telethon Institute for Gene Therapy, HSR-TIGET, Milano, Italy
Universita Vita-Salute San Raffaele, Milano, Italy
* Corresponding author; email: m.roncarolo{at}hsr.it.
Systemic delivery of lentiviral vector (LV) in immunocompetent mice leads to efficient in vivo cell transduction and expression of the encoded protein under the control of the ubiquitous promoter of human cytomegalovirus (CMV). However, anti-transgene immune response results in clearance of transduced cells 4 weeks after injection. T regulatory cells (Tregs), which have been demonstrated to control immune responses in vivo, were tested for their ability to suppress anti-transgene response leading to stable long-term expression. Adoptive transfer of natural CD4+CD25+ Tregs isolated from wt mice or from transgene tolerant transgenic (tg) mice did not suppress the anti-transgene immune response after LV delivery. These data demonstrate that neither increasing the endogenous pool of nTregs nor transferring nTregs selected in a transgene expressing thymus can modulate the immune response and mediate sustained transgene expression. Conversely, adoptive transfer of antigen presenting cells (APC) isolated from transgene tolerant tg mice efficiently reduced the immune response leading to stable LV-encoded protein expression in vivo. Reduction of CD8+ effector T cells was observed in LV-treated mice co-injected with transgene-expressing APC compared to control mice. These data indicate that anti-transgene immune response can be modulated by transgene-expressing APC possibly through deletion of effector T cells.
