Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity
Ryu Watanabe, … , Jörg J. Goronzy, Cornelia M. Weyand
Ryu Watanabe, … , Jörg J. Goronzy, Cornelia M. Weyand
Published June 12, 2017
Citation Information: J Clin Invest. 2017;127(7):2725-2738. https://doi.org/10.1172/JCI92167.
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Research Article Immunology Metabolism Article has an altmetric score of 104

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 4

PKM2 regulates the expression of the immunoinhibitory ligand PD-L1.

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PKM2 regulates the expression of the immunoinhibitory ligand PD-L1. Macr...
Macrophages were generated from patients with CAD and age-matched healthy controls and stimulated with LPS and IFN-γ for 24 hours. In parallel cultures, the PKM2 activator ML265 (50 μM) or the glucose analog 2DG (5 mM) was added as indicated. (A) Gene expression of costimulatory or coinhibitory molecules measured after 24 hours by reverse transcription PCR (RT-PCR). Data are from 7 experiments. (B and C) Surface expression of the coinhibitory ligands PD-L1 and the costimulatory ligand CD86 was measured by flow cytometry. Representative histograms and mean florescence intensity (MFI) from 9 experiments. (D and E) PD-L1 surface expression on activated macrophages from 18 healthy controls and 34 CAD patients measured by flow cytometry. (D) Representative histograms. (E) Summarized data from both study cohorts. (F) Correlation between PD-L1 surface expression on activated macrophages and the number of comorbidities (DM, HTN, HL) for 34 CAD patients. All data represent the mean ± SEM. *P < 0.05 and ***P < 0.001, by 2-way ANOVA (A–C), Mann-Whitney U test (E), and 1-way ANOVA (F).