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

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

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.

MeSH terms

  • Aged
  • B7-H1 Antigen / immunology
  • B7-H1 Antigen / metabolism*
  • Bone Morphogenetic Protein 4 / immunology
  • Bone Morphogenetic Protein 4 / metabolism
  • Coronary Artery Disease / immunology
  • Coronary Artery Disease / metabolism*
  • Coronary Artery Disease / pathology
  • Female
  • Humans
  • Immunity, Cellular*
  • Interferon Regulatory Factor-1 / immunology
  • Interferon Regulatory Factor-1 / metabolism
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Middle Aged
  • Programmed Cell Death 1 Receptor / immunology
  • Programmed Cell Death 1 Receptor / metabolism
  • Pyruvic Acid / immunology
  • Pyruvic Acid / metabolism*
  • Smad1 Protein / immunology
  • Smad1 Protein / metabolism
  • Smad5 Protein / immunology
  • Smad5 Protein / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology

Substances

  • B7-H1 Antigen
  • BMP4 protein, human
  • Bone Morphogenetic Protein 4
  • CD274 protein, human
  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • SMAD1 protein, human
  • SMAD5 protein, human
  • Smad1 Protein
  • Smad5 Protein
  • Pyruvic Acid