PD-1 signals instruct a critical metabolic switch for maintenance of T cell memory

Abstract

Abstract PD-1 is highly expressed on CD8 T cells during activation, both in acute and chronic viral infections. Inhibitory signaling in cytotoxic T cells through the PD-1 axis is well characterized during chronic infections and has led to the development of clinical checkpoint blockade therapies that restore function to otherwise exhausted CD8 T cells. However, the functional significance of transient PD-1 expression on T cells early after activation during acute infections remains yet to be characterized. It is paradoxical that expression of PD-1 (an inhibitory receptor) during activation temporally coincides with rapid proliferation and production of copious amounts of signature effector cytokines (IFN-γ and TNF-α). Our studies using PD-1−/−antigen-specific CD8 T cells revealed an unexpected lack of an inhibitory role for PD-1 early during priming - PD-1−/−T cells exhibited similar proliferation, accumulation, cytotoxicity and polyfunctionality compared to WT T cells. Surprisingly, PD-1−/−T cells underwent precipitous contraction, leading to near ablation of the memory pool. Mechanistically, PD-1−/−memory Tcells showed a severe defect in antigen-independent homeostatic proliferation in vivo, despite identical expression of common gamma-chain cytokine receptors as WT T cells. Notably, PD-1−/−memory T cells failed to optimally switch the critical utilization of glucose to fatty acid as an energy source, which impaired their homeostatic maintenance and resulted in attrition. These findings show a previously unrecognized role of PD-1 signaling in programming a metabolic switch that is critical for the maintenance of memory CD8 T cells and could make it a novel target for manipulating vaccine-induced memory T cell longevity.