Lin, Pin-HungPin-HungLinWong, Weng-InWeng-InWongWang, Yi-LanYi-LanWangHsieh, Meng-PingMeng-PingHsiehCHIA-WEN LULiang, Chieh-YuChieh-YuLiangJui, Sung-HsiangSung-HsiangJuiWu, Fang-YiFang-YiWuPEI-JER CHENHUNG-CHIH YANG2021-07-032021-07-0320181933-0219https://www.scopus.com/inward/record.uri?eid=2-s2.0-85042216681&doi=10.1038%2fs41385-018-0004-9&partnerID=40&md5=1242a04f7944550fa726a51792c060dahttps://scholars.lib.ntu.edu.tw/handle/123456789/568338Peptide-based T cell vaccines targeting the conserved epitopes of influenza virus can provide cross-protection against distantly related strains, but they are generally not immunogenic. Foreign antigen-specific regulatory T (Treg) cells are induced under subimmunogenic conditions peripherally, although their development and role in vaccine-mediated antiviral immunity is unclear. Here, we demonstrated primary vaccination with peptides alone significantly induced antigen-specific Foxp3+ Treg cells, which were further expanded by repeated vaccination with unadjuvanted peptides. Certain adjuvants, including CpG, suppressed the induction and expansion of antigen-specific Treg cells by peptide vaccination. Interestingly, secondary influenza virus infection significantly increased the frequency of preexisting antigen-specific Treg cells, although primary infection barely induced them. Importantly, specific depletion of vaccine-induced antigen-specific Treg cells promoted influenza viral clearance, indicating their inhibitory role in vivo. Immunization with CpG-adjuvanted peptides by the subcutaneous prime-intranasal-boost strategy restricted the recruitment and accumulation of antigen-specific Treg cells in lung, and stimulated robust T cell immunity. Finally, subcutaneous prime-intranasal-boost immunization with CpG-adjuvanted peptides or whole-inactivated influenza vaccines protected mice from heterosubtypic influenza virus infection. In conclusion, antigen-specific Treg cells induced by peptide vaccines attenuate the antiviral immunity against influenza virus infection. CpG-adjuvanted peptide vaccines provide heterosubtypic influenza protection probably by inhibiting Treg development and enhancing T cell immunity. ? 2018 Society for Mucosal Immunology.[SDGs]SDG3influenza vaccine; transcription factor FOXP3; virus antigen; epitope; immunological adjuvant; influenza vaccine; oligodeoxyribonucleotide; subunit vaccine; virus antigen; animal experiment; animal model; animal tissue; antigen specificity; Article; cellular immunity; controlled study; in vivo study; infant; influenza; influenza vaccination; mouse; nonhuman; priority journal; regulatory T lymphocyte; viral clearance; virus attenuation; virus immunity; acute disease; animal; C57BL mouse; human; immunological memory; immunology; immunosuppressive treatment; influenza; lymphocyte activation; Orthomyxoviridae; orthomyxovirus infection; physiology; regulatory T lymphocyte; secondary immunization; transgenic mouse; Acute Disease; Adjuvants, Immunologic; Animals; Antigens, Viral; Epitopes, T-Lymphocyte; Humans; Immunization, Secondary; Immunologic Memory; Immunosuppression; Influenza Vaccines; Influenza, Human; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oligodeoxyribonucleotides; Orthomyxoviridae; Orthomyxoviridae Infections; T-Lymphocytes, Regulatory; Vaccines, Subunitjournal article10.1038/s41385-018-0004-9294674452-s2.0-85042216681