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J Clin Invest. 2017 Jun 30;127(7):2725-2738. doi: 10.1172/JCI92167. Epub 2017 Jun 12.

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

Author information

1
Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
2
Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
3
Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
4
Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
5
Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.

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.

PMID:
28604383
PMCID:
PMC5490755
DOI:
10.1172/JCI92167
[Indexed for MEDLINE]
Free PMC Article

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