Immune checkpoint dysfunction in large and medium vessel vasculitis.
Giant cell arteritis (GCA) is a granulomatous vasculitis of the aorta and its medium-sized branch vessels. CD4 T cells, macrophages, and dendritic cells (DCs) build granulomatous infiltrates that injure the vessel wall and elicit a maladaptive response to injury. Pathological consequences include fragmentation of elastic membranes, destruction of the medial layer, microvascular neoangiogenesis, massive outgrowth of myofibroblasts, and lumen-occlusive intimal hyperplasia. Antigens have been suspected to drive the local activation of vasculitogenic CD4 T cells, but recent data have suggested a more generalized defect in the threshold setting of such T cells, rendering them hyperreactive. Under physiological conditions, immune checkpoints provide negative signals to curb T cell activation and prevent inflammation-associated tissue destruction. This protective mechanism is disrupted in GCA. Vessel wall DCs fail to express the immunoinhibitory ligand programmed cell death ligand-1, leaving lesional T cells unchecked. Consequently, programmed cell death protein-1-positive CD4 T cells can enter the immunoprivileged vessel wall, where they produce a broad spectrum of inflammatory cytokines (interferon-γ, IL-17, and IL-21) and have a direct role in driving intimal hyperplasia and intramural neoangiogenesis. The deficiency of the programmed cell death protein-1 immune checkpoint in GCA, promoting unopposed T cell immunity, contrasts with checkpoint hyperactivity in cancer patients in whom excessive programmed cell death ligand-1 expression paralyzes the function of antitumor T cells. Excessive checkpoint activity is the principle underlying cancer-immune evasion and is therapeutically targeted by immunotherapy with checkpoint inhibitors. Such checkpoint inhibitors, which unleash anticancer T cells and induce immune-related toxicity, may lead to drug-induced vasculitis.
Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California; and.
Ryu
R
Watanabe
Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California; and.
Hui
H
Zhang
Department of Pathology, Stanford University School of Medicine, Stanford, California.
Gerald
G
Berry
Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California; and.
Jörg J
JJ
Goronzy
Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California; and cweyand@stanford.edu.
Cornelia M
CM
Weyand
D000818:Animals; D001158:Arteries / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D013700:Giant Cell Arteritis / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007155:Immunologic Factors / Q000276:immunology; D018448:Models, Immunological; D015398:Signal Transduction / Q000276:immunology*
D016207:Cytokines; D007155:Immunologic Factors
dendritic cell; giant cell arteritis; immune checkpoint; programmed cell death ligand-1; programmed cell death protein-1