Costimulatory ligand 4-1 BBL (CD137L) as an efficient adjuvant for human antiviral cytotoxic T cell responses

摘要

Effective adjuvants capable of inducing strong cytotoxic T cell responses in humans are lacking. In this study, we tested 4-1 BBL as an adjuvant for activation of human memory antiviral CD8 T cell responses ex vivo. A recombinant replication-defective 4-1 BBL adenovirus was used to convert autologous monocytes into efficient antigen-presenting cells after overnight incubation, bypassing the need to generate dendritic cells. Together with viral peptides, 4-1 BBL led to robust memory responses of human Epstein-Barr virus- and influenza virus-specific cytotoxic T cells, with expansion of peptide-specific CD8 effector cells; up-regulation of Bel-X_L, granzyme A, and perforin; enhanced cytotoxic activity; and increased cytokine production. The response was significant even at a 100-fold lower peptide dose, compared with responses obtained with control adenovirus. Adenovirus-delivered B7.1 also expanded and activated virus-specific CDS T cells, but 4-1 BBL was more effective in driving the T- cells toward a more fully differentiated CD27~- effector state. Thus, 4-1 BBL is a promising adjuvant for human memory CD8 T cells and will likely be most effective in the boost phase of a prime-boost strategy.