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

Authors :
Paillon N
Mouro V
Dogniaux S
Maurin M
Saez Pons JJ
Ferran H
Bataille L
Zucchetti AE
Hivroz C
Source :
Science signaling [Sci Signal] 2023 Nov 28; Vol. 16 (813), pp. eadh2456. Date of Electronic Publication: 2023 Nov 28.
Publication Year :
2023

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 <superscript>+</superscript> Jurkat cells or primary human CD8 <superscript>+</superscript> 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.

Details

Language :
English
ISSN :
1937-9145
Volume :
16
Issue :
813
Database :
MEDLINE
Journal :
Science signaling
Publication Type :
Academic Journal
Accession number :
38015913
Full Text :
https://doi.org/10.1126/scisignal.adh2456