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Here we show that the transcription factor SRF, a master regulator of cytoskeletal gene expression, is required for effective IL-2 signalling during <jats:italic>L. monocytogenes<\/jats:italic> infection. Acting cell-autonomously with its actin-regulated cofactors MRTF-A and MRTF-B, SRF is dispensible for initial TCR-mediated CD8<jats:sup>+<\/jats:sup> T cell proliferation, but is required for sustained IL-2 dependent CD8<jats:sup>+<\/jats:sup> effector T cell expansion, and persistence of memory cells. Following TCR activation, <jats:italic>Mrtfab<\/jats:italic>-null CD8<jats:sup>+<\/jats:sup> T cells produce IL-2 normally, but homotypic clustering is impaired both in vitro and in vivo. Expression of cytoskeletal structural and regulatory genes, most notably actins, is defective in <jats:italic>Mrtfab<\/jats:italic>-null CD8<jats:sup>+<\/jats:sup> T cells. Activation-induced cell clustering in vitro requires F-actin assembly, and <jats:italic>Mrtfab<\/jats:italic>-null cell clusters are small, contain less F-actin, and defective in IL-2 retention. Clustering of <jats:italic>Mrtfab<\/jats:italic>-null cells can be partially restored by exogenous actin expression. IL-2 mediated CD8<jats:sup>+<\/jats:sup> T cell proliferation during infection thus depends on the control of cytoskeletal dynamics and actin gene expression by MRTF-SRF signalling.<\/jats:p>","DOI":"10.1038\/s41467-024-52230-8","type":"journal-article","created":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T16:03:07Z","timestamp":1726070587000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["IL-2 delivery to CD8+ T cells during infection requires MRTF\/SRF-dependent gene expression and cytoskeletal dynamics"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3852-0438","authenticated-orcid":false,"given":"Diane","family":"Maurice","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4419-5012","authenticated-orcid":false,"given":"Patrick","family":"Costello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2348-3941","authenticated-orcid":false,"given":"Jessica","family":"Diring","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6180-7292","authenticated-orcid":false,"given":"Francesco","family":"Gualdrini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6985-3090","authenticated-orcid":false,"given":"Bruno","family":"Frederico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9658-0067","authenticated-orcid":false,"given":"Richard","family":"Treisman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,9,11]]},"reference":[{"key":"52230_CR1","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1146\/annurev.immunol.25.022106.141548","volume":"25","author":"MA Williams","year":"2007","unstructured":"Williams, M. 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