TY - JOUR
T1 - The immunoinhibitory PD-1/PD-L1 pathway in inflammatory blood vessel disease
AU - Weyand, Cornelia M.
AU - Berry, Gerald J.
AU - Goronzy, Jörg J.
N1 - Funding Information:
This work was supported by the U.S. National Institutes of Health (grants R01 AR042527, R01 HL117913, R01 AI108906, and P01 HL129941 to C.M.W. and grants R01 AI108891, R01 AG045779, U19 AI057266, R01 AI129191, and I01 BX001669 to J.J.G.) and the Gove-nar and Cahill Discovery Funds. We thank our patients who have provided samples for research studies and our clinical colleagues who have contributed their patients. We apologize to all colleagues whose work could not be included.
Publisher Copyright:
©2017 Society for Leukocyte Biology
PY - 2018/3
Y1 - 2018/3
N2 - 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 lo ; 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 hi , a defect induced by their addiction to glucose and glycolytic breakdown. PD-L1 hi 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.
AB - 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 lo ; 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 hi , a defect induced by their addiction to glucose and glycolytic breakdown. PD-L1 hi 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.
KW - Immune checkpoint
KW - atherosclerosis
KW - coronary artery disease
KW - giant cell arteritis
KW - vasculitis
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U2 - 10.1189/jlb.3MA0717-283
DO - 10.1189/jlb.3MA0717-283
M3 - Article
C2 - 28848042
AN - SCOPUS:85042354396
SN - 0741-5400
VL - 103
SP - 565
EP - 575
JO - Journal of Leukocyte Biology
JF - Journal of Leukocyte Biology
IS - 3
ER -