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.

Enhanced antitumor effect against human telomerase reverse transcriptase (hTERT) by vaccination with chemotactic‐hTERT gene‐modified tumor cell and the combination with anti‐4‐1BB monoclonal antibodies

“…Different tumor models and different treatment modalities have yielded different results. [29][30][31][32][33] Data herein was in sharp contrast to some investigators who claimed that 4-1BB signaling enable CTL priming in the absence of CD4 1 T cells, [29][30][31] but consistent with others who suggested that CD4…”

Costimulation of CD8 T Cell Responses by OX40

“…Similarly, the reduced CTL response to influenza was shown to be at the level of persistence of T cells late in the primary response and to result in a weakened ability of the resultant memory CD8 cells to respond again to recall Ag (30,31). Complimentary data have also been described in systems using agonist Abs, in which provision of 4-1BB signals replaced the need for CD4 cells in an antitumor CD8 response that was normally dependent on CD4 help (32). These data clearly suggest parallels between 4-1BB and OX40 and indicate that each can play an important role in maintaining CD8 cell numbers and/or reactivity over time.…”

IL-15-Dependent Induction of 4-1BB Promotes Antigen-Independent CD8 Memory T Cell Survival

“…However, the location of the 4-1BBL in the unimmunized mouse remains unknown. Although 4-1BBL has been reported on APC following activation with LPS or anti-CD40 (51)(52)(53)(54)(55), it has been difficult to detect on in vivo-activated APC following influenza or lymphocytic choriomeningitis virus infection (M. A. DeBenedette and T. H. Watts, unpublished results). To test whether IL-15 might induce 4-1BBL as well as its receptor, we added IL-15 to collagenase-treated splenocytes and bone marrow-derived immature dendritic cells, but 4-1BBL was not detected (data not shown).…”