4-1BB Signaling Synergizes with Programmed Death Ligand 1 Blockade To Augment CD8 T Cell Responses during Chronic Viral Infection

Emory Vaccine Center, Emory University, Atlanta, GA 30329, USA.
The Journal of Immunology (Impact Factor: 5.36). 08/2011; 187(4):1634-42. DOI: 10.4049/jimmunol.1100077
Source: PubMed

ABSTRACT Previous studies have identified the inhibitory role that the programmed death 1 (PD-1) pathway plays during chronic infection. Blockade of this pathway results in rescue of viral-specific CD8 T cells, as well as reduction of viral loads in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). We tested the effect of combining PD ligand 1 (PD-L1) blockade with an agonistic regimen that induces 4-1BB costimulation during chronic LCMV infection. There is a boosting effect in the rescue of LCMV-specific CD8 T cell responses after dual treatment with PD-L1 blockade and 4-1BB agonistic Abs when the amount and timing of 4-1BB costimulation are carefully controlled. When PD-L1-blocking Abs are given together with a single low dose of anti-4-1BB agonistic Abs, there is an enhanced and stable expansion of viral-specific CD8 T cells. Conversely, when blocking Abs to PD-L1 are given with a repetitive high dose of anti-4-1BB, there is an initial synergistic expansion of viral-specific CD8 T cells by day 7, followed by dramatic apoptosis by day 14. Viral control paralleled CD8 T cell kinetics after dual treatment. By day 7 posttreatment, viral titers were lower in both of the combined regimens (compared with PD-L1 blockade alone). However, whereas the high dose of anti-4-1BB plus PD-L1 blockade resulted in rebound of viral titers to original levels, the low dose of anti-4-1BB plus PD-L1 blockade resulted in a stable reduction of viral loads. These findings demonstrate the importance of carefully manipulating the balance between activating and inhibitory signals to enhance T cell responses during chronic infection.

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Available from: Sang-Jun Ha, Jul 29, 2015
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    • "These data combined have given good rationale for targeting 4- 1BB in immunization or vaccination strategies for viruses as they directly demonstrate that 4-1BB is available to act as a stimulatory receptor. Proof of concept studies targeting 4-1BB with an agonist antibody, or 4-1BBL in a vector, consequently resulted in enhanced CD8 responses to influenza, LCMV, and HSV (Halstead et al., 2002; Kim et al., 2005; Zhang et al., 2007; Moraes et al., 2011; Vezys et al., 2011). "
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