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Signal."],"published-print":{"date-parts":[[2026,6,9]]},"abstract":"<jats:p>\n                    Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is a key negative regulator of T cell activation, acting with C-terminal Src kinase (Csk) to suppress early T cell receptor (TCR) signaling and maintain immune tolerance. Given that the autoimmune disease\u2013associated R620W variant alters T cell responses, we investigated the effects of PTPN22 on T cell activation. We identified a role for PTPN22 in modulating cytoskeletal dynamics at the immunological synapse in Jurkat cells through its interaction with proline-serine-threonine phosphatase\u2013interacting protein 1 (PSTPIP1), a cytoskeletal adaptor protein that recruits actin nucleation\u2013promoting factors, including WASp, to the TCR. PTPN22 deficiency or inhibition disrupted Arp2\/3-dependent actin remodeling, leading to excessive central F-actin foci, PSTPIP1 mislocalization, and enhanced Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling, especially under low-affinity stimulation of the TCR. Super-resolution DNA-PAINT analysis revealed that loss of PTPN22 promoted aberrant PSTPIP1-TCR nanoscale colocalization and increased TCR clustering. These findings uncover a PTPN22-PSTPIP1 signaling axis that is critical for regulating cytoskeletal remodeling and receptor organization, providing insights into T cell hyperactivation that may be relevant to autoimmune disease.\n                  <\/jats:p>","DOI":"10.1126\/scisignal.ady6063","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T17:58:29Z","timestamp":1781027909000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["PTPN22 regulates T cell synapse formation through PSTPIP1-dependent actin remodeling"],"prefix":"10.1126","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8313-8467","authenticated-orcid":true,"given":"Megan D.","family":"Joseph","sequence":"first","affiliation":[{"name":"London Centre for Nanotechnology, University College London, WC1H 0AH London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8206-0178","authenticated-orcid":true,"given":"Cecilia","family":"Zaza","sequence":"additional","affiliation":[{"name":"London Centre for Nanotechnology, University College London, WC1H 0AH London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0545-2092","authenticated-orcid":true,"given":"Olivia P. 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