Deficiency of the CD155-CD96 immune checkpoint controls IL-9 production in giant cell arteritis

Cell Rep Med. 2023 Apr 18;4(4):101012. doi: 10.1016/j.xcrm.2023.101012.


Loss of function of inhibitory immune checkpoints, unleashing pathogenic immune responses, is a potential risk factor for autoimmune disease. Here, we report that patients with the autoimmune vasculitis giant cell arteritis (GCA) have a defective CD155-CD96 immune checkpoint. Macrophages from patients with GCA retain the checkpoint ligand CD155 in the endoplasmic reticulum (ER) and fail to bring it to the cell surface. CD155low antigen-presenting cells induce expansion of CD4+CD96+ T cells, which become tissue invasive, accumulate in the blood vessel wall, and release the effector cytokine interleukin-9 (IL-9). In a humanized mouse model of GCA, recombinant human IL-9 causes vessel wall destruction, whereas anti-IL-9 antibodies efficiently suppress innate and adaptive immunity in the vasculitic lesions. Thus, defective surface translocation of CD155 creates antigen-presenting cells that deviate T cell differentiation toward Th9 lineage commitment and results in the expansion of vasculitogenic effector T cells.

Keywords: CD155; CD96; ER stress; IL-9; T cell; autoimmune vasculitis; autoimmunity; giant cell arteritis; immune checkpoint receptors; macrophage.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptive Immunity
  • Animals
  • Antigens, CD / metabolism
  • Cytokines / metabolism
  • Giant Cell Arteritis* / metabolism
  • Giant Cell Arteritis* / pathology
  • Humans
  • Mice
  • T-Lymphocytes


  • Cytokines
  • Antigens, CD