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PI3K signaling is a critical regulator of T cell function; activating mutations affecting PI3K\u03b4 result in an immunodeficiency with multiple T cell defects. Using mice expressing activated PI3K\u03b4, we found aberrant expression of proinflammatory Th1 signature genes under Th2-inducing conditions, both in vivo and in vitro. This dysregulation was driven by a PI3K\u03b4-IL-2-Foxo1 signaling amplification loop, fueling Foxo1 inactivation, loss of Th2 lineage restriction, and extensive epigenetic reprogramming. Surprisingly, ablation of Fasl, a Foxo1-repressed gene, normalized both Th2 differentiation and TCR signaling. BioID and imaging revealed Fas interactions with TCR signaling components, which were supported by Fas-mediated potentiation of TCR signaling that could occur in the absence of FADD. Our results highlight Fas-FasL signaling as a critical intermediate in phenotypes driven by activated PI3K\u03b4, thereby linking two key pathways of immune dysregulation.<\/jats:p>","DOI":"10.1084\/jem.20252154","type":"journal-article","created":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T07:20:51Z","timestamp":1768634451000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["A PI3K\u03b4-Foxo1-FasL signaling amplification loop rewires CD4+ T cell signaling and differentiation"],"prefix":"10.1084","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2741-3302","authenticated-orcid":true,"given":"Dominic P.","family":"Golec","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health 1 , Bethesda, 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