A first strategy for the blockade of adaptive immunity is obviously to target costimulation pathways and therefore provide an early control on lymphocyte priming. Whereas several costimulatory pathways have now been identified, CD28-mediated T cell costimulation by APC expressing CD80/CD86 molecules from the B7 family is clearly prominent. Indeed, CD28 signaling strongly enhances T cell proliferation and survival, cytokine production and prevents induction of anergy after TCR-mediated activation (Boise et al., 1995) . Consequently, anti-CD80 (B7.1) or anti-CD86 (B7.2) antibodies inhibit T cell priming and genetically engineered CD28-deficient T cells are strongly impaired in their capacity to expand (Green et al., 1994; Salomon and Bluestone, 2001) . T cells activation also promotes up-regulation of the negative regulator CTLA-4, another ligand of CD80 and CD86 molecules, which transmits inhibitory signals that regulate activated T cell and provides a key homeostatic mechanism of the immune response (Fife and Bluestone, 2008) . One of the early striking evidence of the key role of this molecule is that CTLA-4-deficient animal rapidly die FIGURE 4 | Detection of anti-Ova T cells in animals treated with combination therapies. Seven mice per group were injected with 1 × 10 11 vg rAAV2/1-Ova in the gastrocnemius muscles at day 0 and received at the same time combination therapies as in Figure 3 . Splenocytes were then harvested 80 days after and analyzed for the presence of lymphocytes capable to respond to Ova antigen. (A) Splenocytes were analyzed by ELISpot as described in the Section "Materials and Methods" for their capacity to secrete IFNγ after in vitro restimulation with the Ova-derived immunodominant SIINFEKL peptide. (B) 5 × 10 7 Splenocytes from the same mice were also adoptively transferred to 5 Gy-irradiated syngenic mice inoculated 1 day after with Ova-bearing EG7 tumor cells. The capacity of transferred lymphocytes to reject the tumors was monitored three times per week by measuring the tumor size with a digital caliper. www.frontiersin.org from massive lymphoproliferative syndrome and dysregulation of immunity (Waterhouse et al., 1995) .