{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:25:21Z","timestamp":1791350721957,"version":"4.3.1"},"reference-count":39,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"crossref","award":["1220999"],"award-info":[{"award-number":["1220999"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"crossref","award":["1261352"],"award-info":[{"award-number":["1261352"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"crossref","award":["3240581"],"award-info":[{"award-number":["3240581"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"crossref"}]},{"award":["1220999"],"award-info":[{"award-number":["1220999"]}],"id":[{"id":"https:\/\/ror.org\/02ap3w078","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1261352"],"award-info":[{"award-number":["1261352"]}],"id":[{"id":"https:\/\/ror.org\/02ap3w078","id-type":"ROR","asserted-by":"publisher"}]},{"award":["3240581"],"award-info":[{"award-number":["3240581"]}],"id":[{"id":"https:\/\/ror.org\/02ap3w078","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Periodontitis is a chronic inflammatory disease characterized by alveolar bone loss driven by dysregulated immune responses. We previously showed that extracellular vesicles derived from retinoic acid-induced regulatory T lymphocytes (RA-Treg EVs) suppress pathogenic CD4+ T-lymphocyte responses and reduce alveolar bone loss during periodontitis. Herein, we investigated whether RA-Treg EVs also modulate macrophage and CD8+ T-lymphocyte responses during experimental periodontitis. Ligature-induced periodontitis was generated in mice, followed by local administration of RA-Treg EVs. Alveolar bone loss was analyzed by micro-computed tomography, and periodontal tissues and cervical lymph nodes were analyzed by flow cytometry to quantify antigen-presenting cells, macrophages, macrophage subsets, and CD8+ T lymphocytes. The direct effects of RA-Treg EVs on macrophage phenotype and CD8+ T-cell proliferation and activation were assessed in vitro. RA-Treg EV treatment attenuated alveolar bone loss and preserved trabecular microarchitecture. This effect was associated with reduced macrophage infiltration into periodontal tissues, modulation of macrophage polarization, and restoration of CD8+ T-cell abundance in periodontal tissues and draining cervical lymph nodes, without major changes in CD8+IFN-\u03b3+ or CD8+RANKL+ cells. In vitro, RA-Treg EVs induced heterogeneous macrophage phenotypes distinct from the classical M1\/M2 polarization states while markedly enhancing CD8+ T-cell proliferation and activation. These findings indicate that RA-Treg EVs preserve alveolar bone during experimental periodontitis while selectively modulating macrophage and CD8+ T-lymphocyte responses.<\/jats:p>","DOI":"10.3390\/ijms27135845","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:55:11Z","timestamp":1782780911000},"page":"5845","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting Periodontitis with Treg-Derived Extracellular Vesicles: Modulation of Macrophages and CD8+ T-Cell Responses"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4004-3999","authenticated-orcid":false,"given":"Carolina","family":"Rojas","sequence":"first","affiliation":[{"name":"Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380544, Chile"},{"name":"Biomedical Research and Innovation Center, Faculty of Medicine, Universidad de Los Andes, Santiago 7620086, Chile"},{"name":"Department of Growth, Development and Public Health, Faculty of Dentistry, Universidad de los Andes, Santiago 7620086, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8456-6372","authenticated-orcid":false,"given":"Luis","family":"Gonz\u00e1lez-Osuna","sequence":"additional","affiliation":[{"name":"Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380544, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4283-7269","authenticated-orcid":false,"given":"Michelle","family":"Garc\u00eda","sequence":"additional","affiliation":[{"name":"Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380544, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0952-9835","authenticated-orcid":false,"given":"Alfredo","family":"Sierra-Cristancho","sequence":"additional","affiliation":[{"name":"Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380544, Chile"},{"name":"Faculty of Dentistry, Universidad Andres Bello, Santiago 8370134, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis Daniel","family":"Sansores-Espa\u00f1a","sequence":"additional","affiliation":[{"name":"Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380544, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Carvajal","sequence":"additional","affiliation":[{"name":"Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380544, Chile"},{"name":"Department of Conservative Dentistry, Faculty of Dentistry, Universidad de Chile, Santiago 8380544, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesley A.","family":"Smyth","sequence":"additional","affiliation":[{"name":"School of Medicine and Biomedical Sciences, University of West London, London W5 5RF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4070-6169","authenticated-orcid":false,"given":"Karina","family":"Pino-Lagos","sequence":"additional","affiliation":[{"name":"Biomedical Research and Innovation Center, Faculty of Medicine, Universidad de Los Andes, Santiago 7620086, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1391-320X","authenticated-orcid":false,"given":"Rolando","family":"Vernal","sequence":"additional","affiliation":[{"name":"Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380544, Chile"},{"name":"Department of Conservative Dentistry, Faculty of Dentistry, Universidad de Chile, Santiago 8380544, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Alvarez, C., Monasterio, G., Cavalla, F., Cordova, L.A., Hernandez, M., Heymann, D., Garlet, G.P., Sorsa, T., Parnanen, P., and Lee, H.M. 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