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 6

T cell–inhibitory functions of CAD macrophages are mediated by PD-L1.

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T cell–inhibitory functions of CAD macrophages are mediated by PD-L1. (A...
(A–H) Macrophages were generated from CAD patients and cocultured with healthy CD4 T cells. Macrophages were transfected with siRNA specific for PD-L1 (siPD-L1) or control siRNA (siCon). Alternatively, macrophages were incubated with anti–PD-L1 antibodies or an isotype control antibody. In some experiments, the PKM2 activator ML265 (50 μM) was combined with anti–PD-L1 antibodies. Frequencies of activated CD4+CD69+ and CD4+CD25+ T cells were measured by flow cytometry on day 3. T cell proliferation was assessed by CFSE dilution on day 6. (A) Representative flow cytometric contour plots for CD69+ and CD25+ CD4 T cells. (B) Summary of 8 experiments comparing CAD macrophages transfected with either control siRNA or PD-L1–specific siRNA. (C) Representative dot plot of CFSE expression in CD4 T cells captured on day 6. (D) Summarized proliferation indices from 7 experiments are shown. (E–H) The PKM2 activator ML265 was combined with anti–PD-L1 antibodies (aPD-L1). (E and F) T cell activation was measured on day 3 according to the frequency of CD69+ or CD25+ CD4 T cells. Representative contour plots and results from 5 to 6 independent experiments are shown. (G and H) Dilution of CFSE in proliferating CD4 T cells measured by flow cytometry. Representative dot plots and summarized proliferation indices from 7 experiments are shown. Values represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by paired, 2-tailed Student’s t test.