title: In vivo triggering through 4-1BB enables Th-independent priming of CTL in the presence of an intact CD28 costimulatory pathway.
abstract: Triggering of 4-1BB, a member of the TNFR family, through in vivo administration of agonistic anti-4-1BB Ab delivers a powerful costimulatory signal to CTL. We found this signal to effectively replace the need for CD4(+) T cell help in the cross-priming of tumor-specific CTL immunity. Furthermore, 4-1BB Ab can convert an otherwise tolerogenic peptide vaccine into a formulation capable of efficient CTL priming. Initial activation of naive CTL can occur in the absence of 4-1BB costimulation, but this signal permits increased survival of Ag-stimulated CTL. Because naive CTL do not express 4-1BB at their surface, susceptibility to 4-1BB triggering depends on prior up-regulation of this receptor. We show that this requires both stimulation of the TCR and CD28-dependent costimulation. Accordingly, blockade of the CD28-costimulatory pathway abrogates the capacity of agonistic anti-4-1BB Ab to trigger Th-independent CTL immunity. In conclusion, our data reveal that the 4-1BB-mediated survival signal is positioned downstream of Ag-specific TCR triggering and CD28-dependent costimulation of naive CTL. The powerful effects of 4-1BB triggering on the induction, amplification, and persistence of CTL responses provide a novel strategy for increasing the potency of vaccines against cancers.
authors.affiliation: Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Linda
authors.initials: L
authors.lastname: Diehl
authors.forename: Geertje J D
authors.initials: GJ
authors.lastname: van Mierlo
authors.forename: Annemieke T
authors.initials: AT
authors.lastname: den Boer
authors.forename: Ellen
authors.initials: E
authors.lastname: van der Voort
authors.forename: Marieke
authors.initials: M
authors.lastname: Fransen
authors.forename: Liesbeth
authors.initials: L
authors.lastname: van Bostelen
authors.forename: Paul
authors.initials: P
authors.lastname: Krimpenfort
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
authors.forename: Robert
authors.initials: R
authors.lastname: Mittler
authors.forename: Rene E M
authors.initials: RE
authors.lastname: Toes
authors.forename: Rienk
authors.initials: R
authors.lastname: Offringa
mesh_terms: D053330:4-1BB Ligand; D000818:Animals; D015703:Antigens, CD; D018106:CD28 Antigens / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D007106:Immune Sera / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007399:Interphase / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017475:Receptors, Nerve Growth Factor / Q000276:immunology / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D053330:4-1BB Ligand; D015703:Antigens, CD; D018106:CD28 Antigens; D007106:Immune Sera; D008024:Ligands; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; C505975:Tnfsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha