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Immunol."],"abstract":"<jats:p>\n                    The tyrosine kinase ZAP-70 is essential for T-cell activation and development, but the mechanisms regulating its activity remain unclear. Previous studies showed that the Src-family kinase LCK binds phosphorylated tyrosine 319 of ZAP-70 via its SH2 domain. Additionally, a gain-of-function ZAP-70 mutation involving the YEEI motif enhances LCK recruitment and TCR-mediated signaling. To investigate the physiological consequences of enhanced ZAP-70-LCK interaction\n                    <jats:italic>in vivo<\/jats:italic>\n                    , we generated a knock-in mouse model expressing the\n                    <jats:italic>Zap70<\/jats:italic>\n                    <jats:sup>YEEI<\/jats:sup>\n                    gain-of-function mutation. Analysis of thymocyte development revealed that the\n                    <jats:italic>Zap70<\/jats:italic>\n                    <jats:sup>YEEI<\/jats:sup>\n                    mutation altered T-cell maturation, resulting in increased differentiation of thymic regulatory T (Treg) cells and reduced thymic negative selection. In the peripheral T-cell compartment, mutant mice exhibited decreased surface expression of the TCR\u03b1\u03b2 complex and an increased frequency of memory CD4 T cells. These findings indicate that enhancing the ZAP-70-LCK interaction modifies signaling thresholds during thymic selection and peripheral T-cell homeostasis. Collectively, our results demonstrate that a gain-of-function mutation in\n                    <jats:italic>Zap70<\/jats:italic>\n                    significantly reshapes T-cell development and maturation, highlighting the importance of regulated ZAP-70-LCK interactions in establishing immune tolerance and maintaining T-cell compartment balance.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1932213","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:21:20Z","timestamp":1791264080000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A Zap70 gain-of-function mutation alters mouse thymic maturation"],"prefix":"10.3389","volume":"17","author":[{"given":"Inmaculada","family":"Vico-Barranco","sequence":"first","affiliation":[{"name":"Department of Biomedicine, Biotechnology and Public Health, Universidad de C\u00e1diz","place":["C\u00e1diz, Spain"]},{"name":"Centre 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