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

doi:10.1073/pnas.0306567101

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

^†Department of Immunology, University of Toronto, Toronto, ON, Canada M5S 1A8; ^§Department of Microbiology and Immunology, University of Montréal, Montréal, QC, Canada H3C 3J7; and ^¶Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada L8N 3Z5

Edited by Ralph M. Steinman, The Rockefeller University, New York, NY, and approved December 9, 2003 (received for review October 10, 2003)

Abstract

Effective adjuvants capable of inducing strong cytotoxic T cell responses in humans are lacking. In this study, we tested 4-1BBL as an adjuvant for activation of human memory antiviral CD8 T cell responses ex vivo. A recombinant replication-defective 4-1BBL 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, 4-1BBL 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 Bcl-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 CD8 T cells, but 4-1BBL was more effective in driving the T cells toward a more fully differentiated CD27^– effector state. Thus, 4-1BBL 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.

Footnotes

↵ ∥ To whom correspondence should be addressed at: Department of Immunology, University of Toronto, Room 5263, Medical Sciences Building, 1 King's College Circle, Toronto, ON, Canada M5S 1A8. E-mail: tania.watts{at}utoronto.ca.
↵ ‡ J.B. and T.W. contributed equally to this work.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: Adv, adenovirus 5; 4-1BBL-Adv, recombinant replication-defective Adv expressing full-length human 4-1BBL ligand; PBMC, peripheral blood mononuclear cell; EBV, Epstein–Barr virus; APC, antigen-presenting cell; CTL, cytotoxic T lymphocyte.