PD-1 inhibits T cell actin remodeling at the immunological synapse independently of its signaling motifs

• Published in: Science signaling Vol. 16; no. 813; p. eadh2456
• Main Authors: Paillon, Noémie, Mouro, Violette, Dogniaux, Stéphanie, Maurin, Mathieu, Saez Pons, Juan-José, Ferran, Hermine, Bataille, Laurence, Zucchetti, Andrés Ernesto, Hivroz, Claire
• Format: Journal Article
• Language: English
• Published: United States 28.11.2023
• Subjects: Actins - metabolism; B7-H1 Antigen - metabolism; Humans; Immunological Synapses; Lymphocyte Activation; Programmed Cell Death 1 Receptor - metabolism; Signal Transduction
• ISSN: 1937-9145
• DOI: 10.1126/scisignal.adh2456

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.