CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy

The outcome of antigen recognition by naive CD8(+) cytotoxic T lymphocytes (CTLs) in the periphery is orchestrated by CD4(+) T-helper cells, and can e ither lead to priming or tolerization. The presence of T-helper cells favor s the induction of CTL immunity, whereas the absence of T-helper cells can result in CTL tolerance. The action of T helper cells in CTL priming is med iated by CD40-CD40 ligand interactions. We demonstrate here that triggering of CD40 in vivo can considerably enhance the efficacy of peptide-based ant i-tumor vaccines. The combination of a tolerogenic peptide vaccine containi ng a minimal essential CTL epitope with an activating antibody against CD40 converts tolerization into strong CTL priming. Moreover, CD40 ligation can provide an already protective tumor-specific peptide vaccine with the capa city to induce therapeutic CTL immunity in tumor-bearing mice. These findin gs indicate that the CD40-CD40 ligand pair can act as a 'switch', determini ng whether naive peripheral CTLs are primed or tolerized, and support the c linical use of CD40-stimulating agents as components of anti-cancer vaccine s.