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Flightless-1 (FLII) is a gelsolin-family actin regulator with unique leucine-rich repeats that can couple cytoskeletal dynamics to diverse signaling pathways. Here, using conditional knockout mice, we identify essential roles for FLII in both CD8\n                  <jats:sup>+<\/jats:sup>\n                  and regulatory T cells. Loss of FLII in CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells caused a profound loss of naive cells from the spleen, impaired CCR7-dependent migration, and defective accumulation in the lung parenchyma during antigen-specific responses to respiratory vesicular stomatitis virus infection, despite largely preserved activation, effector differentiation, and cytotoxic function. FLII-deficient Foxp3\n                  <jats:sup>+<\/jats:sup>\n                  regulatory T cells maintained normal numbers but exhibited diminished CD25 expression, defective IL-2 signaling, and failed to restrain spontaneous, tissue-specific autoimmunity. These findings identify FLII as a critical and previously unrecognized orchestrator of T cell trafficking and immune regulation, which may link chemokine receptor signaling to actin remodeling and is essential for proper T cell migration and function.\n                <\/jats:p>","DOI":"10.1101\/2025.08.15.669900","type":"posted-content","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T04:55:13Z","timestamp":1755752113000},"source":"Crossref","is-referenced-by-count":1,"title":["Loss of the actin remodeling protein Flightless-1 impairs CD8 and regulatory T cell function"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3854-2919","authenticated-orcid":false,"given":"Michelle M.","family":"Lissner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna M.","family":"Sullivan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2136-3543","authenticated-orcid":false,"given":"Minjian","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"McKenna","family":"Sherve","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2130-3732","authenticated-orcid":false,"given":"Anne M.","family":"Hocking","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5864-5299","authenticated-orcid":false,"given":"Jessica A.","family":"Hamerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9652-7178","authenticated-orcid":false,"given":"Daniel J.","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025082212500543000_2025.08.15.669900v1.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.26.021607.090347"},{"key":"2025082212500543000_2025.08.15.669900v1.2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20131324"},{"key":"2025082212500543000_2025.08.15.669900v1.3","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12716"},{"key":"2025082212500543000_2025.08.15.669900v1.4","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-004-4225-6"},{"key":"2025082212500543000_2025.08.15.669900v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2007.04.011"},{"key":"2025082212500543000_2025.08.15.669900v1.6","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1091\/mbc.E18-03-0147","article-title":"The leucine-rich region of Flightless I interacts with R-ras to regulate cell extension formation","volume":"29","year":"2018","journal-title":"Mol Biol Cell"},{"key":"2025082212500543000_2025.08.15.669900v1.7","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0802260"},{"key":"2025082212500543000_2025.08.15.669900v1.8","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1999.5817"},{"key":"2025082212500543000_2025.08.15.669900v1.9","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1999.0420"},{"key":"2025082212500543000_2025.08.15.669900v1.10","doi-asserted-by":"crossref","unstructured":"Carpentier, S. 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