Immune checkpoint dysfunction in large and medium vessel vasculitis

Am J Physiol Heart Circ Physiol. 2017 May 1;312(5):H1052-H1059. doi: 10.1152/ajpheart.00024.2017. Epub 2017 Mar 17.


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.

Keywords: dendritic cell; giant cell arteritis; immune checkpoint; programmed cell death ligand-1; programmed cell death protein-1.

Publication types

  • Review

MeSH terms

  • Animals
  • Arteries / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • Cytokines / immunology*
  • Giant Cell Arteritis / immunology*
  • Humans
  • Immunity, Innate / immunology*
  • Immunologic Factors / immunology
  • Models, Immunological
  • Signal Transduction / immunology*


  • Cytokines
  • Immunologic Factors