title: Costimulatory ligand 4-1BBL (CD137L) as an efficient adjuvant for human antiviral cytotoxic T cell responses.
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.
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON, Canada M5S 1A8.
authors.forename: Jacob
authors.initials: J
authors.lastname: Bukczynski
authors.forename: Tao
authors.initials: T
authors.lastname: Wen
authors.forename: Kim
authors.initials: K
authors.lastname: Ellefsen
authors.forename: Jack
authors.initials: J
authors.lastname: Gauldie
authors.forename: Tania H
authors.initials: TH
authors.lastname: Watts
mesh_terms: D053330:4-1BB Ligand; D000256:Adenoviridae / Q000235:genetics; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000938:Antigen-Presenting Cells / Q000378:metabolism; D018122:B7-1 Antigen / Q000502:physiology; D018106:CD28 Antigens / Q000032:analysis; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D009975:Orthomyxoviridae / Q000276:immunology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology*
chemical_list: D053330:4-1BB Ligand; D000276:Adjuvants, Immunologic; D018122:B7-1 Antigen; D018106:CD28 Antigens; D011994:Recombinant Proteins; C505974:TNFSF9 protein, human; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D014409:Tumor Necrosis Factor-alpha