Unphosphorylated tyrosines mediate PD-1 inhibition of T cell signaling condensate formation.

Authors

Monica Sharma, Zachary B Katz, David C Dewitt, Kiersten M Ruff, Akashdip Singh, Huan Lan, Wilson Phung, Jeffery Tom, Aimin Song, Jawahar Sudhamsu, John Davies, John G Quinn, Rohit V Pappu, Andrey S Shaw

Published in

Science (New York, N.Y.). Volume 393. Issue 6816. Pages 1145-1151. Sep 10, 2026. Epub Sep 10, 2026.

Abstract

T cell receptor (TCR) engagement stimulates formation of a biomolecular condensate, including the scaffold protein linker of activated T cells (LAT). We investigated whether the immune-inhibitory receptor programmed cell death protein 1 (PD-1) inhibits by impeding TCR-induced LAT condensation. In vitro reconstitutions revealed that the cytoplasmic domain of PD-1 directly inhibited LAT condensation. This inhibitory interaction required tyrosine residues in the two inhibitory motifs of PD-1. Contrary to current working models, tyrosine phosphorylation eliminated PD-1 inhibition. Replacing tyrosine with tryptophan reconstituted PD-1 inhibition in T cells, confirming that phosphorylation does not mediate this effect. These findings support the concept that hydrogen bond-donating aromatic residues within inhibitory motifs provide the primary mechanism that explains how inhibitory receptors disrupt signaling networks and block immune activation.

PMID:
42721241
Bibliographic data and abstract were imported from PubMed on 11 Sep 2026.

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