ÌÇÐÄ´«Ã½

Skip to main content
 
Notice: Users may be experiencing issues with displaying some pages on stanfordhealthcare.org. We are working closely with our technical teams to resolve the issue as quickly as possible. Thank you for your patience.
ÌÇÐÄ´«Ã½

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

ÌÇÐÄ´«Ã½

Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity. The Journal of clinical investigation Watanabe, R. n., Shirai, T. n., Namkoong, H. n., Zhang, H. n., Berry, G. J., Wallis, B. B., Schaefgen, B. n., Harrison, D. G., Tremmel, J. A., Giacomini, J. C., Goronzy, J. J., Weyand, C. M. 2017; 127 (7): 2725–38

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.

View details for