{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T11:48:36Z","timestamp":1791805716426,"version":"4.3.4"},"reference-count":46,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"KAKENHI","doi-asserted-by":"publisher","award":["S 24229004"],"award-info":[{"award-number":["S 24229004"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is a cytosolic tyrosine phosphatase expressed in immune cells that negatively regulates T cell receptor (TCR) signaling and is implicated in autoimmune diseases through a common (R620W) variant. The molecular mechanisms by which PTPN22 modulates TCR activation remain incompletely understood. Here, we show that upon T cell activation, PTPN22 forms delayed clusters at TCR microclusters (MCs) alongside Csk, STS-1, and PSTPIP, constituting a feedback inhibitory complex. Using imaging analyses, mass spectrometry, and knockout mouse models, we demonstrate that this complex functions as a delayed negative regulation of TCR signaling, and that autoimmune-associated PTPN22 (R620W) mutant exhibits reduced binding to Csk and STS-1, impairing complex formation. Consequently, T cells expressing the mutant display enhanced cytokine production and immune responses. These findings reveal a cooperative inhibitory mechanism involving PTPN22 and its partners that modulates T cell activation, providing insights into how PTPN22 variants contribute to autoimmune disease susceptibility.<\/jats:p>","DOI":"10.1093\/intimm\/dxag050","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T07:55:13Z","timestamp":1790322913000},"source":"Crossref","is-referenced-by-count":0,"title":["PTPN22 mediates delayed negative feedback of T cell activation by forming an inhibitory signaling complex"],"prefix":"10.1093","author":[{"given":"Akiko","family":"Hashimoto-Tane","sequence":"first","affiliation":[{"name":"Laboratory of Cell Signaling, RIKEN Center for Integrative Medical Sciences , Yokohama, Kanagawa 230-0045 ,","place":["Japan"]},{"name":"MSD K.K. , Tokyo 102-8667 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Kawashima","sequence":"additional","affiliation":[{"name":"Laboratory of Applied Proteomics Research, Department of Applied Genomics, Kazusa DNA Research Institute , Kisarazu, Chiba 292-0818 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Machie","family":"Sakuma","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Signaling, RIKEN Center for Integrative Medical Sciences , Yokohama, Kanagawa 230-0045 ,","place":["Japan"]},{"name":"Laboratory for Infectious Disease and Immunology, RIKEN Center for Integrative Medical Sciences , Yokohama, Kanagawa 230-0045 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natsumi","family":"Yoneda","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Signaling, RIKEN Center for Integrative Medical Sciences , Yokohama, Kanagawa 230-0045 ,","place":["Japan"]},{"name":"Drug Discovery Structural Biology Platform Unit, RIKEN Center for Integrative Medical Sciences , Yokohama, Kanagawa 230-0045 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natsuko","family":"Tanimura","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Signaling, RIKEN Center for Integrative Medical Sciences , Yokohama, Kanagawa 230-0045 ,","place":["Japan"]},{"name":"Office of the Center Director, RIKEN Center for Integrative Medical Science , Yokohama, Kanagawa 230-0045 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Omics Research, Department of Frontier Research and Development, Kazusa DNA Research Institute , Kisarazu, Chiba 292-0818 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruhiko","family":"Koseki","sequence":"additional","affiliation":[{"name":"Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences , Yokohama, Kanagawa 230-0045 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3328-9571","authenticated-orcid":false,"given":"Osamu","family":"Ohara","sequence":"additional","affiliation":[{"name":"Laboratory of Applied Proteomics Research, Department of Applied Genomics, Kazusa DNA Research Institute , Kisarazu, Chiba 292-0818 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Malissen","sequence":"additional","affiliation":[{"name":"Aix Marseille Universit\u00e9, INSERM, CNRS, Centre D'Immunologie de Marseille-Luminy , Marseille 13009 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9495-3547","authenticated-orcid":false,"given":"Takashi","family":"Saito","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Signaling, RIKEN Center for Integrative Medical Sciences , Yokohama, Kanagawa 230-0045 ,","place":["Japan"]},{"name":"Drug Discovery Structural Biology Platform Unit, RIKEN Center for Integrative Medical Sciences , Yokohama, Kanagawa 230-0045 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"2026101207220819200_dxag050-B1","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1038\/nature05911","article-title":"Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls","volume":"447","author":"The Wellcome Trust Case Control 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