Abstract
Background:T cell function is regulated by complex signaling networks of interconnected activators and inhibitors. Blockade of inhibitory receptors such as programmed death-1 (PD-1) has emerged as a novel treatment for multiple forms of cancer. One of the most common adverse events associated with blockade of the endogenous PD-1/PD-L1 pathway is the induction of autoimmune pathology in multiple tissues, demonstrating that PD-1 activation is necessary for normal immune homeostasis in humans (Kostine, et al., 2018). Given this body of clinical data, we sought to develop a PD-1 agonist antibody as a therapeutic approach to restore immune homeostasis in patients living with autoimmune diseases. PD-1 expression and function has been primarily described on T cells (Ishida, et al., 1992), with additional data available from several other immune cell populations (Ohaegbulam, et al., 2015).Objectives:To study the effect of PD-1 agonism on plasmacytoid dendritic cell (pDC) function.Methods:Human PBMCs stimulated with or without toll-like receptor (TLR)-9 agonist, CpG were analyzed by flow cytometry for PD-1 expression on immune cell subsets. To assess the impact of PD-1 agonist on pDC function human PBMCs were activated by CpG in the presence or absence of PD-1 agonist. Type-I interferon (IFN) levels were quantified using ELISA from culture supernatants. The expression of interferon stimulated genes was analyzed by qPCR as a measure of type-I IFN activation.Results:We have discovered that TLR9 activation can induce PD-1 expression on plasmacytoid dendritic cells, which has not been previously reported. Further, we have demonstrated that PD-1 agonism inhibits TLR9-mediated activation and the effector functions of plasmacytoid dendritic cells.Conclusion:These data suggest the potential of PD-1 as a target for regulating diseases with pathology generated by type-I IFN.
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