Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity
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
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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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 2

CAD macrophages fail to support activation and clonal expansion of CD4 T cells.

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CAD macrophages fail to support activation and clonal expansion of CD4 T...
Macrophages were generated from monocytes from CAD patients and age-matched controls and cocultured with healthy purified CD4 T cells (macrophages: 10,000/well; T cells: 50,000/well). The stimulatory capacity of the macrophages was determined by the induction of CD69 and CD25 on T cells after 72 hours. T cell proliferation was quantified by CFSE dilution. (A) Representative flow cytometric data. (B) Frequencies of CD4+CD69+ and CD4+CD25+ T cells from 8 independent experiments. (C) Inhibitory effect of CAD macrophages on CD45RO– and CD45RO+CD4+ T cell populations. T cell activation was measured by the frequency of CD69+CD4+ T cells. Representative dot blots are shown. (D–F) T cell proliferation was quantified by CFSE dilution on day 6. (D) Representative dot blots. (E) Proliferation indices for 8 healthy controls and 13 patients with CAD. (F) The deficiency of T cell stimulation by CAD macrophages increased with increasing numbers of macrophages, suggestive of an active suppressive mechanism and not a reduced stimulatory capacity. Flow cytometric measurements of CFSE dilution in representative cocultures are shown. All data represent the mean ± SEM. **P < 0.01 and ***P < 0.001, by unpaired, 2-tailed Student’s t test.