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

Watanabe, Ryu; Shirai, Toshikazu; Namkoong, Hong; Zhang, Hui; Berry, Gerald J.; Wallis, Barbara B.; Schaefgen, Benedikt; Harrison, David G.; Tremmel, Jennifer A.; Giacomini, John C.; Goronzy, Jörg J.; Weyand, Cornelia M.

doi:10.1172/jci92167

Cited by 76 publications

(84 citation statements)

References 72 publications

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“…Human atherosclerosis appears to follow different rules than GCA, as recent data strongly support a very active PD‐1 checkpoint in the atherosclerotic plaque (Fig. ).…”

Section: Pd‐l1hi Immunoinhibitory Mϕs In Cadmentioning

confidence: 93%

“…Most Mϕs in atherosclerotic plaques are PD‐L1 + , enabling them to provide inhibitory signals to interacting T cells (Fig. ).…”

Section: Pd‐l1hi Immunoinhibitory Mϕs In Cadmentioning

confidence: 99%

“…Patient‐derived PD‐L1 hi Mϕs suppress the activation and clonal expansion of CD4 T cells. Importantly, they inhibit the induction of IFN‐γ–producing T cells specific for VZV . VZV is a herpesvirus that causes chickenpox during childhood .…”

Section: Pd‐l1hi Immunoinhibitory Mϕs In Cadmentioning

confidence: 99%

“…This is a frequent event in the elderly; by the time people turn 80 yr old, up to 50% of them have experienced VZV reactivation, manifesting clinically as herpes zoster and complicated by postherpetic pain . When stimulated with VZV lysate, 1 million PBMCs from healthy individuals contained 250 IFN‐γ–secreting T cells, whereas patients with CAD had <100 of those protective T cells . Addition of anti–PD‐L1 Abs improved the induction of patient‐derived anti‐VZV T cells by almost 50%, implicating PD‐L1 in inhibiting antiviral immunity.…”

Section: Pd‐l1hi Immunoinhibitory Mϕs In Cadmentioning

confidence: 99%

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The immunoinhibitory PD-1/PD-L1 pathway in inflammatory blood vessel disease

Weyand

Berry

Goronzy

2017

Journal of Leukocyte Biology

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Because of their vital function, the wall structures of medium and large arteries are immunoprivileged and protected from inflammatory attack. That vascular immunoprivilege is broken in atherosclerosis and in vasculitis, when wall-invading T cells and macrophages (Mϕ) promote tissue injury and maladaptive repair. Historically, tissue-residing T cells were studied for their antigen specificity, but recent progress has refocused attention to antigen-nonspecific regulation, which determines tissue access, persistence, and functional differentiation of T cells. The coinhibitory receptor PD-1, expressed on T cells, delivers negative signals when engaged by its ligand PD-L1, expressed on dendritic cells, Mϕ, and endothelial cells to attenuate T cell activation, effector functions, and survival. Through mitigating signals, the PD-1 immune checkpoint maintains tissue tolerance. In line with this concept, dendritic cells and Mϕs from patients with the vasculitic syndrome giant cell arteritis (GCA) are PD-L1 ; including vessel-wall-embedded DCs that guard the vascular immunoprivilege. GCA infiltrates in the arterial walls are filled with PD-1 T cells that secrete IFN-γ, IL-17, and IL-21; drive inflammation-associated angiogenesis; and facilitate intimal hyperplasia. Conversely, chronic tissue inflammation in the atherosclerotic plaque is associated with an overreactive PD-1 checkpoint. Plaque-residing Mϕs are PD-L1 , a defect induced by their addiction to glucose and glycolytic breakdown. PD-L1 Mϕs render patients with coronary artery disease immunocompromised and suppress antiviral immunity, including protective anti-varicella zoster virus T cells. Thus, immunoinhibitory signals affect several domains of vascular inflammation; failing PD-L1 in vasculitis enables unopposed immunostimulation and opens the flood gates for polyfunctional inflammatory T cells, and excess PD-L1 in the atherosclerotic plaque disables tissue-protective T cell immunity.

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“…Human atherosclerosis appears to follow different rules than GCA, as recent data strongly support a very active PD‐1 checkpoint in the atherosclerotic plaque (Fig. ).…”

Section: Pd‐l1hi Immunoinhibitory Mϕs In Cadmentioning

confidence: 93%

“…Most Mϕs in atherosclerotic plaques are PD‐L1 + , enabling them to provide inhibitory signals to interacting T cells (Fig. ).…”

Section: Pd‐l1hi Immunoinhibitory Mϕs In Cadmentioning

confidence: 99%

Section: Pd‐l1hi Immunoinhibitory Mϕs In Cadmentioning

confidence: 99%

Section: Pd‐l1hi Immunoinhibitory Mϕs In Cadmentioning

confidence: 99%

See 2 more Smart Citations

The immunoinhibitory PD-1/PD-L1 pathway in inflammatory blood vessel disease

Weyand

Berry

Goronzy

2017

Journal of Leukocyte Biology

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“…In a follow-up to the glycolytic flux study above, the investigators found that the elevated glycolytic flux in macrophages from CAD subjects leads to excess mitochondrial pyruvate, which drives BMP4- and IRF1-dependent expression of the T cell inhibitory protein PD-L1 (Watanabe et al, 2017). The high PD-L1 expression on these macrophages was shown to block T cell activation, and the investigators correlated this with impaired anti-varicella zoster virus immunity in the CAD patients.…”

Section: Energy Metabolism Affects Immune Cell Function In Atherosclementioning

confidence: 99%

Monocyte-Macrophages and T Cells in Atherosclerosis

2017

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Atherosclerosis is an arterial disease process characterized by the focal subendothelial accumulation of apolipoprotein B-lipoproteins, immune and vascular wall cells, and extracellular matrix. The lipoproteins acquire features of damage-associated molecular patterns and trigger first an innate immune response, dominated by monocyte-macrophages, and then an adaptive immune response. These inflammatory responses often become chronic and non-resolving, leading to arterial damage and thrombosis-induced organ infarction. The innate immune response is regulated at various stages, from hematopoiesis through monocyte changes and macrophage activation. The adaptive immune response is regulated primarily by mechanisms that affect the balance of regulatory vs. effector T cells. Mechanisms related to cellular cholesterol, phenotypic plasticity, metabolism, and aging play key roles in regulating these responses. Herein we review select topics that shed light on these processes and suggest new treatment strategies.

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