One convenient way to pharmacologically block the CD28 costimulation pathway is to use the soluble CD80/CD86 ligand CTLA-4/Ig. This fusion protein prevents CD28 interaction with CD80 and CD86 molecules on naïve and activated T cells and therefore provides a strong and early inhibition on T cell priming (June et al., 1990; Lenschow et al., 1992; Larsen et al., 2005) . CTLA-4/Ig may also induce a negative signalization on the APC side through the induction of indoleamine2,3-dioxygenase (IDO) which catalyses the production of inhibitory kynurenine from tryptophan (Grohmann et al., 2002) . CTLA-4/Ig may also possibly provide some level of APC depletion in vivo, although this aspect has been poorly documented and should critically depend on the form of CTLA-4/Ig used. Importantly, CTLA-4/Ig is now clinically available for the treatment of diseases such as rheumatoid arthritis (Dumont, 2004) and it is thus reasonable to propose its evaluation in the field of gene therapy. Indeed, there has been experimental evidence that CTLA-4/Ig in combination with a monoclonal antibody to CD40L (MR1) in the context of gene therapy can block immune responses and allow vector readministration in the mouse (Halbert et al., 1998; Lorain et al., 2008) . It is difficult to weight the relative roles of CTLA-4/Ig and MR1 in these experiments but a plausible hypothesis is that CTLA-4/Ig provides the strongest immunoregulatory contribution since MR1 alone has been reported to be less efficient in similar experimental conditions (Manning et al., 1998) . The results reported herein are consistent with these earlier reports and provide definitive evidence that CTLA-4/Ig alone efficiently, but only transiently, blocks anti-transgene T cell priming.