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Here, we applied integrated single\u2010cell RNA sequencing and T cell receptor (TCR) profiling to characterize immune responses in a PRRSV vaccination\u2013challenge model spanning complete, partial, and non\u2010protection outcomes. We identified distinct CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell subsets that were selectively enriched in protected animals vaccinated with modified live vaccine (MLV) and marked by clonal expansion, strong cytotoxic transcriptional programs, and enhanced functional activity, which correlated with rapid control of viremia after challenge. In contrast, non\u2010protected animals accumulated dysfunctional CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells expressing exhaustion\u2010associated markers such as CTLA4 despite partial cytotoxic signatures. Mechanistically, the protection\u2010associated responses were primarily driven by viral structural proteins (SP). Replacing the SP\u2010coding region of a heterologous strain reshaped the CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell landscape from a mixed cytotoxic\/exhausted profile toward a protective program, accompanied by improved clinical outcomes. Further, optimal CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell activation required macrophages\/monocytes\u2010derived innate signaling, including TLR4 and TLR8 pathways, and was enhanced by CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell help. Together, our findings define protection\u2010associated CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell states linked to viral control and provide insights for rational PRRSV vaccine design.\n                  <\/jats:p>","DOI":"10.1002\/advs.76732","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T14:48:38Z","timestamp":1785336518000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated Single\u2010Cell and TCR Profiling Reveals Protection\u2010Associated CD8\n                    <sup>+<\/sup>\n                    T Cell Subsets Linked to Viral Control in PRRSV"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3790-0161","authenticated-orcid":false,"given":"Can","family":"Kong","sequence":"first","affiliation":[{"name":"State Key Laboratory of Epigenetic Regulation and Intervention Institute of Biophysics Chinese Academy of Sciences  Beijing China"},{"name":"State Key Laboratory of Veterinary Public Health and Safety  Beijing China"},{"name":"Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs College of Veterinary Medicine China Agricultural University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7281-5837","authenticated-orcid":false,"given":"Siang","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Epigenetic Regulation and Intervention Institute of Biophysics Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4147-139X","authenticated-orcid":false,"given":"Maolin","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Epigenetic Regulation and Intervention Institute of Biophysics Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5963-2462","authenticated-orcid":false,"given":"Meng","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Epigenetic Regulation and Intervention Institute of Biophysics Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailin","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Public Health and Safety  Beijing China"},{"name":"Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs College of Veterinary Medicine China Agricultural University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bolun","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Public Health and Safety  Beijing China"},{"name":"Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs College of Veterinary Medicine China Agricultural University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhua","family":"Xie","sequence":"additional","affiliation":[{"name":"Jinyu Biotechnology Co. 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