Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity
Ryu Watanabe, Tsuyoshi Shirai, Hong Namkoong, Hui Zhang, Gerald J. Berry, Barbara B. Wallis, Benedikt Schaefgen, David G. Harrison, Jennifer A. Tremmel, John C. Giacomini, Jörg J. Goronzy, Cornelia M. Weyand
Ryu Watanabe, Tsuyoshi Shirai, Hong Namkoong, Hui Zhang, Gerald J. Berry, Barbara B. Wallis, Benedikt Schaefgen, David G. Harrison, Jennifer A. Tremmel, John C. Giacomini, Jörg J. Goronzy, Cornelia M. Weyand
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Research Article Immunology Metabolism

Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity

Abstract

Patients with coronary artery disease (CAD) are at high risk for reactivation of the varicella zoster virus (VZV) and development of herpes zoster (HZ). Here, we found that macrophages from patients with CAD actively suppress T cell activation and expansion, leading to defective VZV-specific T cell immunity. Monocyte-derived and plaque-infiltrating macrophages from patients with CAD spontaneously expressed high surface density of the immunoinhibitory ligand programmed death ligand-1 (PD-L1), thereby providing negative signals to programmed death-1+ (PD-1+) T cells. We determined that aberrant PD-L1 expression in patient-derived macrophages was metabolically controlled. Oversupply of the glycolytic intermediate pyruvate in mitochondria from CAD macrophages promoted expression of PD-L1 via induction of the bone morphogenetic protein 4/phosphorylated SMAD1/5/IFN regulatory factor 1 (BMP4/p-SMAD1/5/IRF1) signaling pathway. Thus, CAD macrophages respond to nutrient excess by activating the immunoinhibitory PD-1/PD-L1 checkpoint, leading to impaired T cell immunity. This finding indicates that metabolite-based immunotherapy may be a potential strategy for restoring adaptive immunity in CAD.

Authors

Ryu Watanabe, Tsuyoshi Shirai, Hong Namkoong, Hui Zhang, Gerald J. Berry, Barbara B. Wallis, Benedikt Schaefgen, David G. Harrison, Jennifer A. Tremmel, John C. Giacomini, Jörg J. Goronzy, Cornelia M. Weyand

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Figure 10

Proposed model connecting the pyruvate metabolic checkpoint with PD-L1 expression.

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Proposed model connecting the pyruvate metabolic checkpoint with PD-L1 e...
In healthy macrophages (left), PKM2 is in active tetrameric form. Glycolytic flux is high, but pyruvate is mostly processed into lactate, lowering mitochondrial respiration. Macrophages from patients with CAD (middle) dimerize PKM2, lowering its activity and effectively reducing glycolytic flux and lactate production. Reduced glycolytic flux leads to the accumulation of glycolytic intermediates such as glucose 6-phosphate (G6P), glyceraldehyde 3-phosphate (GA3P), and 3-phosphoglycerate (3PG), which are used for biosynthetic purposes. Enhanced transport of pyruvate into the mitochondria causes mitochondrial stress and excess ROS production. Mitochondrial pyruvate sustains the production of BMP4 and downstream activation of the transcription factor IRF1, thereby upregulating surface expression of PD-L1. ML265 forces PKM2 into active tetrameric form (right), restores glycolytic flux, and promotes the interconversion of pyruvate into lactate. This reduces pyruvate transport into the mitochondria, eases mitochondrial stress, and prevents BMP4 induction. The end result is a normalization of PD-L1 expression. PEP, phosphoenolpyruvate; P-lipids, phospholipids.