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 9

Pyruvate controls PD-L1 expression via the BMP4/IRF1 axis.

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Pyruvate controls PD-L1 expression via the BMP4/IRF1 axis. (A) Frozen se...
(A) Frozen sections of carotid plaque were immunostained with anti-CD68 (red), anti-BMP4 (green), and DAPI (blue) and analyzed by fluorescence microscopy. Yellow arrows indicate BMP4-expressing macrophages. Scale bars: 200 μm. (B–G) Macrophages from healthy individuals and patients with CAD were stimulated with LPS and IFN-γ. As indicated, exogenous pyruvate (5 mM) was added. Alternatively, the cells were treated with the pyruvate transport inhibitor UK5099 (2 μM). (B–E) Excess pyruvate upregulates BMP4, IRF1, and PD-L1 in healthy macrophages. BMP4 and IRF1 transcript levels were measured by RT-PCR (B and C), and PD-L1 surface expression was assessed by flow cytometry (D and E). Results are from 6 experiments. (F and G) Inhibition of pyruvate transport into the mitochondria reduced PD-L1 expression. Macrophages from healthy individuals and patients with CAD were treated with the pyruvate transporter inhibitor UK5099 (2 μM). Surface PD-L1 expression was analyzed by flow cytometry. Results are from 7 experiments. All data represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by paired, 2-tailed Student’s t test (B and C) and 2-way ANOVA (E and G).