In vivo triggering through 4-1BB enables TH-independent priming of CTL in the presence of an intact CD28 costimulatory pathway

Linda Diehl, Geertje J. D. van Mierlo, Annemieke T. den Boer, Ellen van der Voort, Marieke Fransen, Liesbeth van Bostelen, Paul Krimpenfort, Cornelis J. M. Melief, Robert Mittler, Rene E. M. Toes, Rienk Offringa

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77 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)3755-3762
JournalJournal of Immunology
Issue number8
Publication statusPublished - 2002
Externally publishedYes

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