title: 4-1BB signaling synergizes with programmed death ligand 1 blockade to augment CD8 T cell responses during chronic viral infection.
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.
authors: Emory Vaccine Center, Emory University, Atlanta, GA 30329, USA.
authors: Vaiva
authors: V
authors: Vezys
authors: Pablo
authors: P
authors: Penaloza-MacMaster
authors: Daniel L
authors: DL
authors: Barber
authors: Sang-Jun
authors: SJ
authors: Ha
authors: Bogumila
authors: B
authors: Konieczny
authors: Gordon J
authors: GJ
authors: Freeman
authors: Robert S
authors: RS
authors: Mittler
authors: Rafi
authors: R
authors: Ahmed
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D018122:B7-1 Antigen / Q000276:immunology* / Q000378:metabolism; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D005260:Female; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000378:metabolism; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D010455:Peptides / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D019562:Viral Load
chemical_list: D057134:Antibodies, Neutralizing; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; D010455:Peptides; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9