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

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 3

Activation of PKM2 corrects the inhibitory function of CAD macrophages.

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Activation of PKM2 corrects the inhibitory function of CAD macrophages. ...
Healthy CD4 T cells were cocultured with LPS/IFN-γ–stimulated macrophages generated from patients with CAD who were pretreated with vehicle or the PKM2 activator ML265 (50 μM). Induction of the T cell activation markers CD25 and CD69 was measured by flow cytometry after 72 hours. (A) Representative contour plots. (B) Frequencies of CD4+CD25+ and CD4+CD69+ T cells from 7 independent experiments. (C) Purified CD4 T cells were stained with CFSE and cocultured with vehicle or ML265-pretreated macrophages. Proliferation of CD4 T cells was analyzed by CFSE dilution on day 6. Proliferation indices are from 7 independent experiments. (D and E) Commitment of CD4 T cells to IFN-γ or IL-17 production after coculture with vehicle or ML265-pretreated macrophages was measured by intracellular cytokine staining on day 7. (D) Representative dot plots. (E) Frequencies of CD4+IFN-γ+ and CD4+IL-17+ T cells from 6 independent experiments. All data represent the mean ± SEM. *P < 0.05 and **P < 0.01, by paired, 2-tailed Student’s t test.