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To further elucidate the protective immune mechanisms mediated by T cells and develop novel candidate vaccines with cross-protective potential, multiple CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell epitopes were identified targeting FMDV nonstructural proteins 2B and 2C in the infected pigs. Given its critical role in dendritic cells targeting and enhancing antigen presentation, CD40L was fused with T-\/B-cell epitopes to construct a dendritic cell-targeting broad-spectrum T-cell epitope trimer antigen Trimer-CD40L-TB. When compared to the control antigen Trimer-B (only B-cell epitopes), both Trimer-CD40L-TB and CD40L-free Trimer-TB effectively stimulated multifunctional CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell responses and significantly enhanced humoral immunity induced by the FMDV GH-Loop peptide, which provided more effective broad-spectrum protection against FMDV serotypes A and O. The underlying mechanisms involved Th1 response activation, memory T-cell differentiation, germinal center formation, and high-level NAb production. The synergy between epitope-specific T cells and humoral immunity is key to protective immune responses. This study presents a novel strategy for the development of broad-spectrum vaccines against FMDV.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell epitopes of the nonstructural proteins 2B and 2C of foot-and-mouth disease virus (FMDV) were systematically characterized using FMDV-infected swine combined with intracellular cytokine staining and IFN-\u03b3 ELISpot assays. The highly conserved epitopes 2C 157\u2013174 and 2C 109\u2013126, identified across seven FMDV serotypes, were recognized by both swine and cattle T cells. This discovery will aid in the development of universal FMDV vaccines capable of eliciting cross-serotype and cross-species immunity. Unlike conventional FMDV vaccines that rely on humoral responses, the trimeric vaccine Trimer-CD40L-TB, integrating CD40L-enhanced T cells, was engineered with conserved B-\/T-cell epitopes. This design not only induced broad-spectrum Th1\/cytotoxic T-cell responses but also improved germinal center formation and neutralizing antibody production, leading to cross-protection against serotypes O and A. This approach demonstrated that T-cell-mediated immunity is essential for durable and cross-serotype protection, thereby offering a blueprint for next-generation vaccines.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.03586-25","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T13:00:12Z","timestamp":1775480412000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["T cell responses to nonstructural proteins promote cross-serotype immunity to foot-and-mouth disease virus"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6795-7710","authenticated-orcid":false,"given":"Suyu","family":"Mu","sequence":"first","affiliation":[{"name":"State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of 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