Abstract 1564 The Common G78R Variant in PILRA Impairs PILRA`s Ability to Suppress Immune Cell Activity

The Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) serves as a cell surface inhibitory receptor, recognizing specific O-glycosylated proteins and transmitting signals through its immunoreceptor tyrosine-based inhibitory motif (ITIM) to suppress immune cell activation. A common missense variant (G78R, rs1859788) in PILRA causes a 4-fold reduction in binding affinity for PILRA ligands. In this study, we investigated whether the G78R variant impacts the ability of PILRA to suppress immune cell activation either in a novel PILRA reporter cell assay in Jurkat cells or in phagocytosis assays in THP-1 cells. In addition to testing the G78R variant, we also tested the R126A mutation or the YY269/298AA mutations to abolish ligand interaction or ITIM phosphorylation, respectively. In the reporter cell assay, PILRA suppressed ITAM (immunoreceptor tyrosine-based activation motif)-dependent luciferase expression in a ligand-dependent and ITIM-dependent manner. Furthermore, the ITAM-suppressing activity of the G78R variant was severely compromised. In THP-1 cells, inducible PILRA expression reduced phagocytic uptake of multiple substrates in an ITIM-dependent manner. Our preliminary data indicates that PILRA's ability to reduce phagocytic uptake is also ligand-dependent and is impaired by the G78R variant.Our findings provide the first evidence that the common G78R variant of PILRA negatively impacts the ability of PILRA to suppress immune cell activity. Thanks for the funding from BrightFocus Foundation.