The PD-1:PD-L1 axis in Inflammatory Arthritis

Abstract

The activation of antigen specific T cells during an immune response is a tightly regulated process at the level of both costimulatory and coinhibitory receptors. One such coinhibitory receptor or checkpoint inhibitor which has received much attention in the field of oncology is the programmed cell death protein 1 (PD-1). Blockade of PD-1 or its ligand PD-L1 has proven successful in the treatment of a wide variety of cancers, therefore highlighting an important role for this pathway in anti-tumour immune responses. However, a caveat of PD-1 therapy and boosting anti-tumour immune responses is the development of self-reactive T cells which can lead to the induction of various autoimmune or inflammatory diseases, referred to as immune- related adverse events (irAEs). The emergence of rheumatological irAEs such as Inflammatory Arthritis (IA) in recent years has highlighted the importance of PD-1 in maintaining self-tolerance. Furthermore, the emergence of rheumatology related irAEs raises an important question as to how defects in this pathway can contribute to spontaneous rheumatological disease. In this review, we describe the biological distribution, function and regulation of the PD-1 pathway, its potential role in IA and irAE related IA.

Keywords: Adverse events; Checkpoint inhibitors; PD-1; Psoriatic arthritis; Rheumatoid arthritis.

Fig. 1

Mechanisms of action of PD-1. During immunological synapse formation, ligation of PD-1 with PD-L1 leads to the recruitment of SHP-2 at the ITSM site of PD-1 and subsequent dephosphorylation of PI3K, AKT and RAS dampening down TCR mediated signalling, top left panel. Due to inhibition of PI3K and RAS, PD-1 can change the metabolic profile of the T cell by limiting GLUT-1 expression and mitochondrial availability of glucose, favouring fatty acid oxidation over glycolysis, top right panel. There is a paucity of data on the role of B cell PD-1, however it has been suggested that PD-1 leads to inhibition of SYK resulting in reduced B cell proliferation and cytokine production following B cell receptor (BCR) mediated activation, bottom left panel. A recently proposed mechanism of action for macrophage PD-1 expression is binding to PDL-1 in cis and therefore limiting available PD-L1 for ligation with T cell PD-1, bottom right panel

Fig. 2

The PD-1 pathway in Inflammatory Arthritis. Despite increased expression of PD-1 by CD4+ and CD8+ T cells in the synovial tissue of RA patients, increased sPD-1 and PD-1 carrying EV could inhibit PD-1 mediated T cell suppression. Additionally, availability of PD-L1 by synovial DC could be limited due to increased expression of CD80 and the binding of CD80 to PD-L1 in cis, therefore, reducing the functionally available PD-L1