Background/Purpose: Giant cell arteritis (GCA) is an autoimmune syndrome characterized by granuloma formation in the media of medium and large arteries. In a healthy immune system, excessive immune stimulation is counteracted by negative costimulatory signals which oppose T cell activation and protect tissue tolerance. An important inhibitory molecule within the B7/CD28 family is the programmed death-1 receptor (PD-1), with its ligand PD-L1. We have screened T cells from GCA patients for molecular elements that regulate inhibitory pathways and have tested the functional role of co-inhibitory molecules in in vitro and in vivo models of vasculitis.

Methods: Peripheral blood T cells from 45 patients with biopsy-proven GCA and 54 age-matched controls were profiled for the expression of positive and negative costimulatory receptors which critically adjust T cell-responsiveness. Transmural migration of activated T cells was studied in 3-dimensional cellulose fiber-based scaffolds populated with endothelial cells or vascular smooth muscle cells and assembled into walls mimicking human medium arteries. Disease-relevant functions of patient-derived CD4 T cells were studied in vivo in humanized chimera mice engrafted with human arteries. 

Results: GCA patients have significantly increased frequencies of PD-1⁺ CD4 T cells when compared to controls (30.3 % vs. 19.7 %; p=0.02). The PD-1 ligand PD-L1, normally strongly expressed on endothelial cells of the vasa vasorum was barely detectable in GCA-affected temporal arteries. PD-1-PD-L1 interactions were critically involved in regulating transfer of T cells across the endothelial barrier in the 3D-custom made arterial walls. Antibody-mediated blockade of PD-1 doubled the number of CD4 T cells crossing the endothelial layer (n=7 distinct T cell donors; p=0.04) and enhanced pooling of intrawall T cells. To explore the significance of negative signaling in arteritis, human artery-SCID chimeras were treated with the PD-1 blocking PD-L1 fusion protein. Disrupting PD-1 signaling effectively accelerated vessel wall inflammation; by enhancing T cell pooling and DC activation and boosting the production of innate and adaptive cytokines.

Conclusion:  The PD-1-PD-L1 pathway protects the vessel wall from inflammatory attack. Several steps of the immune activation cascade relevant for GCA underlie regulation by this negative signaling pathway. T cells from GCA patients receive insufficient inhibitory signals due to a lack of PD-L1 expression. Reestablishing negative signaling may be necessary to prevent detrimental immune responses in GCA and to restore the immune privilege of the arterial wall.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/impairment-of-the-inhibitory-pd-1-pd-l1-axis-in-giant-cell-arteritis-gca/