{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T08:16:10Z","timestamp":1768896970887,"version":"3.49.0"},"reference-count":35,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2017,12,18]],"date-time":"2017-12-18T00:00:00Z","timestamp":1513555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology","award":["16K19134"],"award-info":[{"award-number":["16K19134"]}]},{"name":"Promotion project from Agency for Medical Research and Development","award":["16fk0108112h0301"],"award-info":[{"award-number":["16fk0108112h0301"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Induction of immunoglobulin (Ig) A in the mucosa of the upper respiratory tract and the nasal cavity protects against influenza virus infection. Cyclic dinucleotides (CDNs) are used as mucosal adjuvants to enhance the immunogenicity of intranasal influenza hemagglutinin (HA) vaccines. The adjuvant activity of 2\u20323\u2032 cyclic guanosine monophosphate\u2013adenosine monophosphate (cGAMP) on Ig production was investigated in nasal-associated lymphoid tissue (NALT), serum of wild-type C57BL\/6J, and stimulator of interferon genes (STING)-deficient mice, which do not recognize cGAMP. Mice were vaccinated intranasally with a HA vaccine with or without the cGAMP adjuvant. IgA and IgG production, T-cell responses, germinal center formation, and cytokine expression in NALT were assayed. cGAMP enhanced IgA and IgG production, and promoted T-cell responses. Intranasal administration of cGAMP activated both NALT and systemic immune cells, induced a favorable cytokine environment for IgA induction, and promoted germinal center formation. The cGAMP effect was STING-dependent. Taken together, cGAMP as an HA vaccine adjuvant promoted a STING-dependent NALT environment suitable for the enhancement of IgA production.<\/jats:p>","DOI":"10.3390\/medsci5040035","type":"journal-article","created":{"date-parts":[[2017,12,19]],"date-time":"2017-12-19T03:54:32Z","timestamp":1513655672000},"page":"35","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["cGAMP Promotes Germinal Center Formation and Production of IgA in Nasal-Associated Lymphoid Tissue"],"prefix":"10.3390","volume":"5","author":[{"given":"Hiromi","family":"Takaki","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan"},{"name":"Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, South 1, West 17, Chuo-ku, Sapporo 060-8556, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken","family":"Takashima","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyuki","family":"Oshiumi","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan"},{"name":"Department of Immunology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjyo, Chuou-ku, Kumamoto 860-0811, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akira","family":"Ainai","sequence":"additional","affiliation":[{"name":"Department of Pathology, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku, Tokyo 162-8640, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tadaki","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Pathology, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku, Tokyo 162-8640, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideki","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Department of Pathology, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku, Tokyo 162-8640, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Misako","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0808-5710","authenticated-orcid":false,"given":"Tsukasa","family":"Seya","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,12,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.chom.2015.02.012","article-title":"Influenza vaccines: Challenges and solutions","volume":"17","author":"Houser","year":"2015","journal-title":"Cell Host Microbe"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"165","DOI":"10.7883\/yoken.JJID.2015.560","article-title":"Intranasal inactivated influenza vaccines: A reasonable approach to improve the efficacy of influenza vaccine?","volume":"69","author":"Tamura","year":"2016","journal-title":"Jpn. J. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2910","DOI":"10.1128\/JVI.79.5.2910-2919.2005","article-title":"Synthetic double-stranded RNA poly(I:C) combined with mucosal vaccine protects against influenza virus infection","volume":"79","author":"Ichinohe","year":"2005","journal-title":"J. Virol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6276","DOI":"10.1016\/j.vaccine.2009.04.074","article-title":"PolyI:PolyC12U adjuvant-combined intranasal vaccine protects mice against highly pathogenic H5N1 influenza virus variants","volume":"27","author":"Ichinohe","year":"2009","journal-title":"Vaccine"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.vaccine.2011.10.058","article-title":"Intranasal administration of a flagellin-adjuvanted inactivated influenza vaccine enhances mucosal immune responses to protect mice against lethal infection","volume":"30","author":"Hong","year":"2012","journal-title":"Vaccine"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Blaauboer, S.M., Mansouri, S., Tucker, H.R., Wang, H.L., Gabrielle, V.D., and Jin, L. (2015). The mucosal adjuvant cyclic di-GMP enhances antigen uptake and selectively activates pinocytosis-efficient cells in vivo. eLife, 4.","DOI":"10.7554\/eLife.06670"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1038\/nri1439","article-title":"NALT-versus PEYER\u2019S-patch-mediated mucosal immunity","volume":"4","author":"Kiyono","year":"2004","journal-title":"Nat. Rev. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Takaki, H., Kure, S., Oshiumi, H., Sakoda, Y., Suzuki, T., Ainai, A., Hasegawa, H., Matsumoto, M., and Seya, T. (2017). Toll-like receptor 3 in nasal CD103+ dendritic cells is involved in immunoglobulin A production. Mucosal. Immunol.","DOI":"10.1038\/mi.2017.48"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/nature07317","article-title":"STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling","volume":"455","author":"Ishikawa","year":"2008","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1038\/nature08476","article-title":"STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity","volume":"461","author":"Ishikawa","year":"2009","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"492","DOI":"10.4049\/jimmunol.1301812","article-title":"MPYS\/STING-mediated TNF-\u03b1, not type I IFN, is essential for the mucosal adjuvant activity of (3\u2032\u20135\u2032)-cyclic-di-guanosine-monophosphate in vivo","volume":"192","author":"Blaauboer","year":"2014","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.cell.2013.04.025","article-title":"One-step generation of mice carrying mutations in multiple genes by CRISPR\/Cas-mediated genome engineering","volume":"153","author":"Wang","year":"2013","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1016\/j.bbrc.2016.09.021","article-title":"STING in tumor and host cells cooperatively work for NK cell-mediated tumor growth retardation","volume":"478","author":"Takashima","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1126\/science.1232458","article-title":"Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway","volume":"339","author":"Sun","year":"2013","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3705","DOI":"10.4049\/jimmunol.1500780","article-title":"PU.1 expression in T follicular helper cells limits CD40L-dependent germinal center B cell development","volume":"195","author":"Awe","year":"2015","journal-title":"J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1128\/CVI.00119-07","article-title":"The bacterial second messenger cdiGMP exhibits promising activity as a mucosal adjuvant","volume":"14","author":"Ebensen","year":"2007","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"\u0160krnjug, I., Guzm\u00e1n, C.A., Rueckert, C., and Ruecker, C. (2014). Cyclic GMP-AMP displays mucosal adjuvant activity in mice. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0110150"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1016\/j.jid.2016.05.105","article-title":"Natural STING agonist as an \u201cIdeal\u201d Adjuvant for cutaneous vaccination","volume":"136","author":"Wang","year":"2016","journal-title":"J. Investig. Dermatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4973","DOI":"10.1016\/j.vaccine.2011.04.094","article-title":"Intranasal c-di-GMP-adjuvanted plant-derived H5 influenza vaccine induces multifunctional Th1 CD4+ cells and strong mucosal and systemic antibody responses in mice","volume":"29","author":"Madhun","year":"2011","journal-title":"Vaccine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1126\/science.271.5253.1289","article-title":"Role of lymphotoxin and the type I TNF receptor in the formation of germinal centers","volume":"271","author":"Matsumoto","year":"1996","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1084\/jem.183.5.2367","article-title":"Differentiation of follicular dendritic cells and full antibody responses require tumor necrosis factor receptor-1 signaling","volume":"183","author":"Bluethmann","year":"1996","journal-title":"J. Exp. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/nature13608","article-title":"RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis","volume":"513","author":"Dannappel","year":"2014","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"29165","DOI":"10.1038\/srep29165","article-title":"RNA is an adjuvanticity mediator for the lipid-based mucosal adjuvant, endocine","volume":"6","author":"Hayashi","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5210","DOI":"10.1016\/j.vaccine.2011.05.026","article-title":"Bis-(3\u2032,5\u2032)-cyclic dimeric adenosine monophosphate: Strong Th1\/Th2\/Th17 promoting mucosal adjuvant","volume":"29","author":"Ebensen","year":"2011","journal-title":"Vaccine"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.cellimm.2012.07.006","article-title":"Evidence for cyclic diguanylate as a vaccine adjuvant with novel immunostimulatory activities","volume":"278","author":"Gray","year":"2012","journal-title":"Cell. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/ni805","article-title":"Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP","volume":"3","author":"Soumelis","year":"2002","journal-title":"Nat. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/nri2322","article-title":"The regulation of IgA class switching","volume":"8","author":"Cerutti","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/cmi.2008.12","article-title":"Human TSLP-Educated DCs","volume":"5","author":"Wang","year":"2008","journal-title":"Cell. Mol. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1111\/imr.12552","article-title":"IL-33: Biological properties, functions, and roles in airway disease","volume":"278","author":"Drake","year":"2017","journal-title":"Immunol. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.jim.2013.10.012","article-title":"Identification of a cell line producing high levels of TSLP: Advantages for screening of anti-allergic drugs","volume":"402","author":"Segawa","year":"2014","journal-title":"J. Immunol. Methods"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1002\/jmv.21824","article-title":"Intranasal administration of adjuvant-combined vaccine protects monkeys from challenge with the highly pathogenic influenza A H5N1 virus","volume":"82","author":"Ichinohe","year":"2010","journal-title":"J. Med. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1111\/j.1600-065X.2008.00737.x","article-title":"Innate immunity to virus infection","volume":"227","author":"Takeuchi","year":"2009","journal-title":"Immunol. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1002\/eji.200323797","article-title":"Toll-like receptor expression in murine DC subsets: Lack of TLR7 expression by CD8 alpha+ DC correlates with unresponsiveness to imidazoquinolines","volume":"33","author":"Edwards","year":"2003","journal-title":"Eur. J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Matsumoto, M., Tatematsu, M., Nishikawa, F., Azuma, M., Ishii, N., Morii-Sakai, A., Shime, H., and Seya, T. (2015). Defined TLR3-specific adjuvant that induces NK and CTL activation without significant cytokine production in vivo. Nat. Commun., 6.","DOI":"10.1038\/ncomms7280"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.1016\/j.celrep.2017.05.015","article-title":"A TLR3-specific adjuvant relieves innate resistance to PD-L1 blockade without cytokine toxicity in tumor vaccine immunotherapy","volume":"19","author":"Takeda","year":"2017","journal-title":"Cell Rep."}],"container-title":["Medical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3271\/5\/4\/35\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:54:26Z","timestamp":1760208866000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3271\/5\/4\/35"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,12,18]]},"references-count":35,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["medsci5040035"],"URL":"https:\/\/doi.org\/10.3390\/medsci5040035","relation":{},"ISSN":["2076-3271"],"issn-type":[{"value":"2076-3271","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,12,18]]}}}