{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T19:03:20Z","timestamp":1791486200898,"version":"4.3.4"},"reference-count":55,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,10,9]]},"abstract":"\n BACKGROUND:<\/jats:title>\n \n CD8\n +<\/jats:sup>\n (cluster of differentiation 8) T cells contribute to atherosclerosis, but how they affect VSMCs (vascular smooth muscle cells) is unclear. The protective role of CD8\n +<\/jats:sup>\n regulatory T cells (Tregs) and in vivo induction strategies also remain undefined.\n <\/jats:p>\n <\/jats:sec>\n \n METHODS:<\/jats:title>\n \n We analyzed human atherosclerosis single-cell RNA sequencing to map immune-VSMC communication. Atherosclerosis was modeled in adeno-associated virus\u2013\n Pcsk9<\/jats:italic>\n or\n Apoe<\/jats:italic>\n \n \u2013\/\u2013<\/jats:italic>\n <\/jats:sup>\n mice. CD8\n +<\/jats:sup>\n T-cell activity was modulated by adoptive transfer of CD45.1\n +<\/jats:sup>\n CD8\n +<\/jats:sup>\n T cells into syngeneic CD45.2\n +<\/jats:sup>\n Apoe<\/jats:italic>\n \n \u2013\/\u2013<\/jats:italic>\n <\/jats:sup>\n recipients (gain-of-function) or nonlytic anti-CD8\u03b1 antibodies (loss-of-function). VSMC-specific Notch loss was tested in\n Myh11<\/jats:italic>\n \n CreER<\/jats:italic>\n <\/jats:sup>\n ;Rbpj<\/jats:italic>\n \n fl\/fl<\/jats:italic>\n <\/jats:sup>\n ;Apoe<\/jats:italic>\n \n \u2013\/\u2013<\/jats:italic>\n <\/jats:sup>\n mice. Ligand-receptor interactions were perturbed with neutralizing antibodies. Lineage tracing was performed using\n Myh11<\/jats:italic>\n \n CreER<\/jats:italic>\n <\/jats:sup>\n ;Rosa26<\/jats:italic>\n \n YFP<\/jats:italic>\n <\/jats:sup>\n ;Apoe<\/jats:italic>\n \n \u2013\/\u2013<\/jats:italic>\n <\/jats:sup>\n mice. CD8\n +<\/jats:sup>\n CD44\n +<\/jats:sup>\n CD122\n +<\/jats:sup>\n Tregs were adoptively transferred to assess therapeutic potential. Transcription factor chromatin immunoprecipitation sequencing (ChIP-seq) was used to define VSMC gene regulation.\n <\/jats:p>\n <\/jats:sec>\n \n RESULTS:<\/jats:title>\n \n CD8\n +<\/jats:sup>\n T cells are the dominant immune partners communicating with VSMCs via CD8\u03b1 in human plaques. Transferred CD8\n +<\/jats:sup>\n T cells localize to the media and inhibit VSMC Notch signaling. VSMC Notch ablation accelerates atherosclerosis, enhancing VSMC proliferation, inflammation, and phenotypic switching. CD8\u03b1 blockade induces CD8\n +<\/jats:sup>\n CD44\n +<\/jats:sup>\n CD122\n +<\/jats:sup>\n Tregs, which, partly via IL-10 (interleukin-10), activate VSMC Notch, suppress proliferation, and limit VSMC-to-macrophage transdifferentiation. These Tregs express higher Notch ligands than conventional CD8\n +<\/jats:sup>\n T cells and decline with a high-cholesterol diet. Their adoptive transfer slows atherosclerosis progression. Blocking Notch1-Jag2 (Jagged 2), or synergistically blocking DLL1\/4 (delta-like ligand 1\/4) and Jag1\/2, negates Treg protection. Mechanistically, Notch-RBPJ (recombination signal binding protein for immunoglobulin kappa J region) activates\n Hes1<\/jats:italic>\n (\n hairy and enhancer of split 1<\/jats:italic>\n ), which suppresses\n Klf4<\/jats:italic>\n (\n Kr\u00fcppel-like factor 4<\/jats:italic>\n ) and\n Rel<\/jats:italic>\n via Hes1\/EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit)\u2013mediated trimethylation of histone H3 at lysine 27 (H3K27me3).\n <\/jats:p>\n <\/jats:sec>\n \n CONCLUSIONS:<\/jats:title>\n \n CD8\n +<\/jats:sup>\n T cells promote atherosclerosis by inhibiting VSMC Notch; CD8\n +<\/jats:sup>\n CD44\n +<\/jats:sup>\n CD122\n +<\/jats:sup>\n Tregs restore Notch, preserve VSMC quiescence, and stabilize plaques. The CD8\n +<\/jats:sup>\n Treg-Notch axis is a novel and promising therapeutic target against atherosclerosis.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/circresaha.126.328918","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T09:00:21Z","timestamp":1788944421000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Inducing CD8\n +<\/sup>\n Tregs Limits Atherosclerosis via Notch-Mediated VSMC Quiescence"],"prefix":"10.1161","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1183-4708","authenticated-orcid":true,"given":"Wentao","family":"Gao","sequence":"first","affiliation":[{"name":"CAS CEMCS-CUHK Joint Laboratory for Cardiovascular Sciences, Department of Chemical Pathology, Li Ka Shing Institute of Health Science (W.G., Y.H., J.L., C.K.H., K.O.L.), Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China."},{"name":"Department of Surgery (W.G., J.Y.W.L.), Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5341-7999","authenticated-orcid":true,"given":"Yangfeng","family":"Hou","sequence":"additional","affiliation":[{"name":"CAS CEMCS-CUHK Joint Laboratory for Cardiovascular Sciences, Department of Chemical Pathology, Li Ka Shing Institute of Health Science (W.G., Y.H., J.L., C.K.H., K.O.L.), Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxing","family":"Liu","sequence":"additional","affiliation":[{"name":"CAS CEMCS-CUHK Joint Laboratory for Cardiovascular Sciences, Department of Chemical Pathology, Li Ka Shing Institute of Health Science (W.G., Y.H., J.L., C.K.H., K.O.L.), Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng Kiu","family":"Ho","sequence":"additional","affiliation":[{"name":"CAS CEMCS-CUHK Joint Laboratory for Cardiovascular Sciences, Department of Chemical Pathology, Li Ka Shing Institute of Health Science (W.G., Y.H., J.L., C.K.H., K.O.L.), Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfred Sze-Lok","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7519-6720","authenticated-orcid":true,"given":"Herman","family":"Waldmann","sequence":"additional","affiliation":[{"name":"Sir William Dunn School of Pathology, University of Oxford, United Kingdom 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