Abstract
The inhibitory receptor programmed cell death 1 (PD-1) plays a major role in functional exhaustion of T cells during chronic infections and cancer, and recent clinical data suggest that blockade of the PD-1 pathway is an effective immunotherapy in treating certain cancers. Thus, it is important to define combinatorial approaches that increase the efficacy of PD-1 blockade. To address this issue, we examined the effect of IL-2 and PD-1 ligand 1 (PD-L1) blockade in the mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection. We found that low-dose IL-2 administration alone enhanced CD8+ T cell responses in chronically infected mice. IL-2 treatment also decreased inhibitory receptor levels on virus-specific CD8+ T cells and increased expression of CD127 and CD44, resulting in a phenotype resembling that of memory T cells. Surprisingly, IL-2 therapy had only a minimal effect on reducing viral load. However, combining IL-2 treatment with blockade of the PD-1 inhibitory pathway had striking synergistic effects in enhancing virus-specific CD8+ T cell responses and decreasing viral load. Interestingly, this reduction in viral load occurred despite increased numbers of Tregs. These results suggest that combined IL-2 therapy and PD-L1 blockade merits consideration as a regimen for treating human chronic infections and cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies / administration & dosage
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Antibodies / pharmacology
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Antiviral Agents / administration & dosage
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Antiviral Agents / pharmacology
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Arenaviridae Infections / drug therapy*
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Arenaviridae Infections / immunology
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Arenaviridae Infections / virology
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B7-H1 Antigen / antagonists & inhibitors*
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B7-H1 Antigen / immunology
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / virology
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Chronic Disease
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Drug Synergism
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Female
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Humans
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Hyaluronan Receptors / metabolism
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Immunologic Factors / administration & dosage
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Immunologic Factors / pharmacology
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Immunotherapy
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Interleukin-2 / administration & dosage*
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Interleukin-2 / pharmacology
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Interleukin-7 Receptor alpha Subunit / metabolism
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Lymphocyte Activation
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Lymphocytic choriomeningitis virus / drug effects
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Lymphocytic choriomeningitis virus / immunology*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Programmed Cell Death 1 Receptor / metabolism
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology
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Viral Load / drug effects
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Viremia / drug therapy
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Viremia / immunology
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Viremia / virology
Substances
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Antibodies
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Antiviral Agents
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B7-H1 Antigen
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Cd274 protein, mouse
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Cd44 protein, mouse
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Hyaluronan Receptors
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Immunologic Factors
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Interleukin-2
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Interleukin-7 Receptor alpha Subunit
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Programmed Cell Death 1 Receptor