{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T10:14:31Z","timestamp":1770891271005,"version":"3.50.1"},"posted":{"date-parts":[[2025,8,20]]},"group-title":"In Review","reference-count":0,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T00:00:00Z","timestamp":1755648000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,13]]},"abstract":"<title>Abstract<\/title>\n        <p>Regulatory T (Treg) cells are potent immunosuppressors of conventional \u03b1\u03b2 T-cells in the tumor microenvironment, but how they may affect innate-like \u03b3\u03b4 T-cells remains poorly understood. Here we show that induced Treg depletion in mice selectively unleashes V\u03b31+ \u03b3\u03b4 T-cells, the main subset of IFN\u03b3-producing \u03b3\u03b4 T-cells, which are required for tumor control in an orthotopic breast cancer model. Treg cells outcompete IFN\u03b3+ \u03b3\u03b4 T-cells for IL-2 due to increased expression of the high-affinity IL-2 receptor, thereby limiting the proliferation and effector functions of IFN\u03b3+ \u03b3\u03b4 T-cells. Consistently, in vivo neutralization of IL-2 alongside Treg depletion abrogates the induction of IFN\u03b3+ \u03b3\u03b4 T-cell responses, whereas administration of an IL-2R\u03b2\u03b3c agonist circumvents Treg-mediated suppression and enhances tumor control. Finally, Treg cells also inhibit endogenous and expanded human \u03b3\u03b4 T-cells, which can be rescued by IL-2R\u03b2\u03b3c agonism to enhance therapeutic responses in xenografted mice. Thus, bypassing Treg-mediated suppression may improve the outcome of \u03b3\u03b4 T-cell-based immunotherapies.<\/p>","DOI":"10.21203\/rs.3.rs-7365467\/v1","type":"posted-content","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T06:38:28Z","timestamp":1755671908000},"source":"Crossref","is-referenced-by-count":1,"title":["Regulatory T cells sabotage antitumor \u03b3\u03b4 T cells by creating IL-2-deficient environments"],"prefix":"10.21203","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4141-9302","authenticated-orcid":false,"given":"Bruno","family":"Silva-Santos","sequence":"first","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine, Universidade de Lisboa"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2448-8699","authenticated-orcid":false,"given":"Rafael","family":"Blanco-Dom\u00ednguez","sequence":"additional","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine"}]},{"given":"Sofia","family":"Mensurado","sequence":"additional","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine"}]},{"given":"Andr\u00e9 Vaz Pinto","family":"Santos","sequence":"additional","affiliation":[{"name":"1 Gulbenkian Institute for Molecular Medicine, Lisbon, Portugal. 2 Current address: Institute of Systems Immunology, Hamburg Center for Translational Immunology, University Medical Center Hamburg-Ep"}]},{"given":"Leandro","family":"Barros","sequence":"additional","affiliation":[{"name":"1 Gulbenkian Institute for Molecular Medicine, Lisbon, Portugal"}]},{"given":"No\u00eblla","family":"Lopes","sequence":"additional","affiliation":[{"name":"Centre d\u2019Immunologie de Marseille-Luminy"}]},{"given":"Mariana","family":"Carreira","sequence":"additional","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine, Lisbon, Portugal"}]},{"given":"Beatriz","family":"Alves","sequence":"additional","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine, Lisbon, Portugal"}]},{"given":"Carlos","family":"Lab\u00e3o-Almeida","sequence":"additional","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine, Lisbon, Portugal"}]},{"given":"Julie","family":"Ribot","sequence":"additional","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine, Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6594-8917","authenticated-orcid":false,"given":"Gon\u00e7alo","family":"Bernardes","sequence":"additional","affiliation":[{"name":"University of Cambridge"}]}],"member":"297","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/www.researchsquare.com\/article\/rs-7365467\/v1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.researchsquare.com\/article\/rs-7365467\/v1.html","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T15:22:55Z","timestamp":1757949775000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.researchsquare.com\/article\/rs-7365467\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,20]]},"references-count":0,"URL":"https:\/\/doi.org\/10.21203\/rs.3.rs-7365467\/v1","relation":{},"subject":[],"published":{"date-parts":[[2025,8,20]]},"subtype":"preprint"}}