Targeting 4-1BB (CD137) to enhance CD8 T cell responses with poxviruses and viral antigens

Abstract

Attenuated vaccinia virus (VACV) vectors are considered prime vaccine candidates for use in immunotherapy of infectious disease. In spite of this, recent data show that the level of attenuation may hamper the efficient generation of protective CD8 T cells. This suggests that additional adjuvant-like activities may need to be combined with attenuated VACV for optimal vaccination. Stimulatory reagents to the TNFR family molecule 4-1BB (CD137) may represent such an adjuvant for vaccination. Previous murine studies have found that 4-1BB can participate in optimal priming of effector and memory CD8 T cells in response to several virus infections, and concordantly direct stimulation of 4-1BB with agonist reagents effectively boosts the CD8 T cell response against those viruses. In contrast, we recently reported that 4-1BB plays no role in the response to a virulent strain of VACV, questioning whether agonists of 4-1BB will be useful adjuvants for vaccination with VACV vectors. Here we show that agonist anti-4-1BB strongly enhanced the primary viral-specific effector CD8 T cell response during infection with live virulent VACV and attenuated VACV, and during immunization with VACV peptides given in IFA. However, accumulation of memory CD8 T cells was enhanced only following infection with virulent VACV or with peptide vaccination, but not with attenuated VACV, correlating in part with more transient expression of 4-1BB on CD8 T cells with attenuated virus. Our data therefore suggest that 4-1BB may be a promising candidate for targeting as an adjuvant for short-term enhancement of CD8 T cell responses with VACV vaccine strategies, but additional receptors may need to be engaged with 4-1BB to allow long-term CD8 T cell immunity with attenuated VACV vectors.

Aging Converts Innate B1a Cells into Potent CD8+ T Cell Inducers

“…Induction of TNFR2 expression on human CD8 + T cells was evaluated after 24 h activation with beads coupled with anti-CD3/CD28 or anti-CD3/CD28/CD137 Abs at 1:30 bead to cell ratio (Invitrogen), or with soluble anti-CD3 (1.5 μg/ml, clone HIT3a; BD Pharmingen) and anti-CD28 (1.5 μg/ml, clone 37.51; BD Pharmingen) and 4-1BB agonistic 3H3 Ab as described elsewhere (40). Alternatively, 4-1BBL + B cells were cultured overnight with eFluor® 450-labeled CD8 + T cells from young mice at a 1:1 ratio in the presence of 1.5 μg/ml soluble anti-CD3 Ab.…”

Differential Impact of CD27 and 4-1BB Costimulation on Effector and Memory CD8 T Cell Generation following Peptide Immunization

“…Although the lack of CD27 signaling results in suboptimal CD8 T cell responses (12,(14)(15)(16)(17), deliberate triggering of CD27 by administration of soluble rCD70 (18) or through transgenic expression of CD70 on DCs (19) prevents tolerance induced by injection of a peptide Ag and allows the generation of a population of effector and memory CD8 T cells. Similarly, 4-1BB triggering was shown to prevent peptide-induced CD8 T cell tolerance (20) and augment effector and memory responses following peptide or DC immunization (21)(22)(23).…”

Targeting CD137 Enhances Vaccine-Elicited Anti–Respiratory Syncytial Virus CD8+ T Cell Responses in Aged Mice

“…The addition of α-41BB mAb treatment increased CD8 + T cell immune responses during influenza secondary responses (37). Recently, mice treated with α-41BB mAb enhanced poxvirus-specific effector CD8 + T cells during infection with attenuated vaccinia virus vectors or with an immunization strategy with vaccinia virus peptides (38). Although the requirement and stage of response for 41BB activity was variable across these studies, the data provided a good rational for targeting 41BB in vaccination strategies for viruses as they demonstrate that 41BB stimulation can act as an adjuvant.…”

“…We administered 100 μg α-41BB mAb for prime and boost. The effect of a lower dose of α-41BB (25 μg) was superior to a higher dose of α-41BB (100 μg or 150 μg) in the study of attenuated vaccinia virus vector (38). As other cell types such as CD4 + T cells, NK cells, NKT cells, and dendritic cells also express 41BB on their surface besides activated CD8 + T cells, we could not rule out the possibility that excessive amounts of α-41BB would be harmful by triggering other cell types (38, 40).…”

“…The effect of a lower dose of α-41BB (25 μg) was superior to a higher dose of α-41BB (100 μg or 150 μg) in the study of attenuated vaccinia virus vector (38). As other cell types such as CD4 + T cells, NK cells, NKT cells, and dendritic cells also express 41BB on their surface besides activated CD8 + T cells, we could not rule out the possibility that excessive amounts of α-41BB would be harmful by triggering other cell types (38, 40). An alternative and likely reason that coadministraion of α-41BB failed to completely rescue TriVax efficacy in aged mice is that other immune mechanisms such as innate and humoral responses would be involved in RSV susceptibility in the aged mouse model.…”