Journal
JOURNAL OF IMMUNOLOGY
Volume 195, Issue 3, Pages 1054-1063Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1403237
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Funding
- National Institutes of Health [AI007245, AI07387, AI078526, AI096040]
- Ragon Institute of MGH, MIT and Harvard
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [U19AI078526, T32AI007245, U19AI096040, T32AI007387] Funding Source: NIH RePORTER
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In various models of chronic infections and cancers, blockade of the inhibitory programmed cell death-1 (PD-1) pathway has been shown to be promising at restoring immune function. However, there is not a complete understanding of the factors that influence responsiveness to programmed death-ligand 1 (PD-L1) blockade. In particular, it is currently unclear whether the efficacy of PD-L1 blockade is dependent on the stage of disease. In a model of chronic lymphocytic choriomeningitis virus infection in mice, we show that exhausted CD8 T cells during the late stage of infection are refractory to rescue by PD-L1 blockade. Interestingly, PD-L1 blockade during the late stage of infection resulted in a biased expansion of PD-1(+) CTLA-4(+) regulatory T cells (Tregs) over antiviral CD8 T cells. Although previous studies have shown that Treg ablation can enhance the immune rescue by PD-L1 blockade, this regimen may induce lethal autoimmunity. In this report, we show that PD-L1 blockade together with CD4 T cell depletion effectively rescued deeply exhausted CD8 T cells and enhanced antiviral control during the late stage of chronic infection without any associated mortality. These data demonstrate the pleiotropic effects of anti-PD-L1 therapy on both virus-specific CD8 T cells and Tregs, and suggest a novel strategy for effectively rescuing deeply exhausted CD8 T cells.
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