Abstract
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.
Original language | English (US) |
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Article number | 101012 |
Journal | Cell Reports Medicine |
Volume | 4 |
Issue number | 4 |
DOIs | |
State | Published - Apr 18 2023 |
Keywords
- CD155
- CD96
- ER stress
- IL-9
- T cell
- autoimmune vasculitis
- autoimmunity
- giant cell arteritis
- immune checkpoint receptors
- macrophage
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology