Gene therapy for muscular dystrophies and other monogenic diseases aims at achieving long-term expression of a functional form of an otherwise deficient gene in target tissues. In this context, the product of the therapeutic gene is structurally different from its abnormal or absent counterpart, and consequently viewed as nonself by the immune system. Additional signals from the viral vector may further strengthen adverse innate and adaptive immune reactions against the transgene product, while the vector itself can be targeted by antiviral pre-existing or acquired immunity. Although the presence of natural epitopes in the non-mutated regions of the protein or the occasional occurrence of mutation reversion in a minute population of patients' cells (Klein et al., 1992) may yield some level of immunological tolerance, it remains that acquired immunity to the transgene product still represents one of the major obstacles to the success of gene therapy. Here, we provide the proof of principle that a combination immunoregulatory therapy targeting two non-redundant checkpoints of the immune response, i.e., priming and effector functions, can promote persistence of transduced target cells and transgene transcription thereof even when some cytotoxic T cells have escaped initial control.