Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8+ T Cell Exhaustion

Bertram Bengsch et al. Immunity (2016) 45:358-373.

Speaker: Yi-Ling Soong (宋宜綾)           Time: 15:10-16:00, Jun. 14, 2017

Commentator: Dr. Pin Ling (凌斌老師)       Place: Room 601

Abstract

In the states of prolonged antigen exposure and inflammation, e.g., chronic viral infection and cancers, T cells exhibit an exhausted phenotype with high expression of inhibitory receptors (including programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)), global transcriptional alteration, and poor effector functions.¹ Since metabolic reprogramming and bioenergetic refueling are required for establishing effector functions of T cells, exhausted T cells (Tex) may be dysregulated in the metabolic/bioenergetics aspects. Indeed, in vitrostudies suggest the effects of PD-1 and CTLA-4 on metabolic reprogramming of T cells.² However, the relations among the inhibitory receptors, bioenergetic metabolism and T cell exhaustion in vivo remain unclear. In this study, the authors used a mouse model of chronic lymphocyticchoriomeningitis virus infection to address this question. They found that, before T cell exhaustion is fully established, the early Tex cells already show mitochondrial abnormalities and bioenergetic insufficiencies, which persist till the final exhaustion state. The bioenergetic insufficiencies of Texcells result from, at least in part, the PD-1/ Programmed death-ligand 1 (PD-L1) pathway and persistent mTOR signaling. PD-1 promotes early metabolic depression and downregulates Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a key transcriptional regulator of metabolism. PD-L1 blockade or PD-1 knockout reverses the metabolic depression of developing Tex cells. Importantly, overexpression of PGC-1α reverses the metabolic depression and improves effector functions of T cells. Therefore, bioenergetic refueling may be a potential strategy to reverse T cell exhaustion and benefit therapies to chronic infection or cancers.

References

1.         E. John Wherry et al. Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection. Immunity (2007) 27:670.

2. Nikolaos Patsoukis1 et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat. Commun. (2015) 6:6692.