PD-1 inhibits T cell actin remodeling at the immunological synapse independently of its signaling motifs
Noémie Paillon, Violette Mouro, Stéphanie Dogniaux, Mathieu Maurin, Juan José Sáez, Hermine Ferran, Laurence Ardouin, Andrés E. Zucchetti, Claire Hivroz
Abstract
Engagement of the receptor programmed cell death molecule 1 (PD-1) by its ligands PD-L1 and PD-L2 inhibits T cell–mediated immune responses. Blocking such signaling provides the clinical effects of PD-1–targeted immunotherapy. Here, we investigated the mechanisms underlying PD-1–mediated inhibition. Because dynamic actin remodeling is crucial for T cell functions, we characterized the effects of PD-1 engagement on actin remodeling at the immunological synapse, the interface between a T cell and an antigen-presenting cell (APC) or target cell. We used microscopy to analyze the formation of immunological synapses between PD-1 + Jurkat cells or primary human CD8 + cytotoxic T cells and APCs that presented T cell–activating antibodies and were either positive or negative for PD-L1. PD-1 binding to PD-L1 inhibited T cell spreading induced by antibody-mediated activation, which was characterized by the absence of the F-actin–dense distal lamellipodial network at the immunological synapse and the Arp2/3 complex, which mediates branched actin formation. PD-1–induced inhibition of actin remodeling also prevented the characteristic deformation of T cells that contact APCs and the release of cytotoxic granules. We showed that the effects of PD-1 on actin remodeling did not require its tyrosine-based signaling motifs, which are thought to mediate the co-inhibitory effects of PD-1. Our study highlights a previously unappreciated mechanism of PD-1–mediated suppression of T cell activity, which depends on the regulation of actin cytoskeleton dynamics in a signaling motif–independent manner.