Session Type: Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Giant cell arteritis (GCA) is a medium and large vessel vasculitis with pathognomonic granulomatous infiltrates in the vessel wall. During the early stages of vasculitis, the bone marrow accelerates myelopoiesis, providing critical effector cells that control T cell immunity via antigen-presenting function. GCA macrophages are distinguished from healthy cells by the low expression of the checkpoint molecules PD-L1 and CD155. Here, we have defined macrophage profiles of co-stimulatory and co-inhibitory ligands and have tested the functional implications of co-stimulation/co-inhibition on T cell differentiation.
Methods: Monocytes from the peripheral blood of GCA patients and age-matched controls were differentiated into monocyte-derived macrophages (MDM) with M-CSF and polarized with LPS/IFN-γ. Patients with granulomatosis with polyangiitis (GPA) served as disease controls. Ligand expression was measured by flow cytometry or by immunofluorescence staining in granulomatous tissue lesions. Cellular protein expression was analyzed by immunoblotting and immunoprecipitation.
Results: Compared to age-matched controls and GPA patients, MDM from GCA patients were strongly positive for CD80/CD86 but expressed low levels of PD-L1 (p=0.0035) and CD155 (p=0.0005). Healthy MDM were consistently double positive for PD-L1 and CD155, but GCA patients had a population of PD-L1low CD155low and of PD-L1neg CD155low MDM. Combined PD-L1/CD155 low expression was maintained in tissue macrophages in inflamed arteries. PD-L1 and CD155 mRNA transcripts were equally abundant in patients and controls and immunoblotting demonstrated similar amounts of total CD155 protein in GCA and control MDM. Subcellular mapping studies with organelle specific markers placed CD155 into the endoplasmic reticulum in GCA MDM and immunoprecipitation experiments confirmed that CD155 protein was retained by ER membranes (p=0.004 GCA vs. control). Transcriptomic studies identified an ER stress signature in GCA MDM, and tunicamycin-induced ER stress was sufficient to cause CD155 retention in healthy MDM (p=0.008). We explored whether the low surface expression of PD-L1 and CD155 had functional consequences. CD155low MDM shifted the differentiation of interacting CD4+ T cells, favoring the expansion of poorly differentiated multifunctional memory T cells.Anti-CD155 blocking antibodies produced a similar bias in T cell differentiation (p< 0.001). Defective expression of the inhibitory ligands was resistant to immunosuppressive therapy and persisted in steroid treated patients.
Conclusion: Patients with GCA generate abnormal antigen-presenting cells that are characterized by the lack of inhibitory ligands. The defect is shared by at least two checkpoints, involving PD-L1- and CD155-dependent signaling. Underlying molecular defects map to the endoplasmic reticulum, which traps PD-L1 and CD155 in the cytosol and prevents surface translocation. PD-L1low CD155low macrophages function as immuno-permissive antigen-presenting cells, supporting the unopposed expansion of multifunctional, pro-inflammatory effector T cells.
To cite this abstract in AMA style:Ohtsuki S, Wang C, Watanabe R, Zhang H, Akiyama M, Warrington K, Berry G, Goronzy J, Weyand C. Immuno-permissive Antigen-presenting Cells in Giant Cell Arteritis [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/immuno-permissive-antigen-presenting-cells-in-giant-cell-arteritis/. Accessed .
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/immuno-permissive-antigen-presenting-cells-in-giant-cell-arteritis/