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Because PAG undergoes palmitoylation, which positions it within plasma membrane lipid rafts, and contains a carboxyl-terminal PDZ-binding motif that connects to the actin cytoskeleton, PAG is a potential target for modulating immune function. Here, we investigated how PAG functioned with actin to regulate T cell immune synapse organization and function. We found that the dynamics of PAG and actin were closely synchronized during immune synapse maturation. Mutation of the PDZ-binding motif of PAG disrupted the PAG-actin interaction, impairing immune synapse formation, stability, and function. To assess the function of the PDZ-binding motif of PAG in vivo, we used mouse models of type IV hypersensitivity and highly immunogenic cancer. In both cases, mice with T cells expressing mutant PAG lacking this motif showed reduced immune responses, particularly in terms of cytotoxicity. These results highlight the importance of the PAG-actin connection for optimal formation and function of the T cell immune synapse. Our research indicates that targeting PAG may be a promising approach to improving immunotherapy in those patients who do not respond or experience immune-related adverse events.<\/jats:p>","DOI":"10.1126\/scisignal.aef0327","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:58:11Z","timestamp":1790099891000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["PAG supports T cell immune synapse function by binding to actin"],"prefix":"10.1126","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2186-5647","authenticated-orcid":true,"given":"Emily K.","family":"Moore","sequence":"first","affiliation":[{"name":"Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA."},{"name":"Division of Rheumatology, Department of Medicine, Columbia University Medical Center, New York, NY 10032, 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