{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:01:20Z","timestamp":1790355680080,"version":"4.1.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2015,4,1]],"date-time":"2015-04-01T00:00:00Z","timestamp":1427846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>We have examined the molecular pathways involved in the adjuvant action of cholera toxin (CT) and two novel nontoxic molecules, multiple-mutated CT (mmCT) and double-mutant heat-labile toxin (dmLT) on human T cell responses. Human PBMCs or isolated monocytes were stimulated in vitro with CT, mmCT, or dmLT plus a polyclonal stimulus (staphylococcal enterotoxin B) or specific bacterial Ags, and effects on expression of cytokines and signaling molecules were determined. CT, mmCT, and dmLT strongly enhanced IL-17A and to a lesser extent IL-13 responses, but had little effect on IFN-\u03b3 production or cell proliferation. Intracellular cytokine staining revealed that the enhanced IL-17A production was largely confined to CD4+ T cells and coculture experiments showed that the IL-17A promotion was effectively induced by adjuvant-treated monocytes. Relative to CT, mmCT and dmLT induced at least 100-fold lower levels of cAMP, yet this cAMP was enough and essential for the promotion of Th17 responses. Thus, inhibition of cAMP-dependent protein kinase A was abolished, and stimulation with a cAMP analog mimicked the adjuvant effect. Furthermore, CT, mmCT, and dmLT induced IL-1\u03b2 production and caspase-1 activation in monocytes, which was associated with increased expression of key proinflammatory and inflammasome-related genes, including NLRP1, NLRP3, and NLRC4. Inflammasome inhibition with a specific caspase-1 inhibitor, or blocking of IL-1 signaling by IL-1 receptor antagonist, abrogated the Th17-promoting effect. We conclude that CT, mmCT, and dmLT promote human Th17 responses via cAMP-dependent protein kinase A and caspase-1\/inflammasome\u2013dependent IL-1 signaling.<\/jats:p>","DOI":"10.4049\/jimmunol.1401633","type":"journal-article","created":{"date-parts":[[2015,3,19]],"date-time":"2015-03-19T02:34:11Z","timestamp":1426732451000},"page":"3829-3839","source":"Crossref","is-referenced-by-count":72,"title":["Cholera Toxin, and the Related Nontoxic Adjuvants mmCT and dmLT, Promote Human Th17 Responses via Cyclic AMP\u2013Protein Kinase A and Inflammasome-Dependent IL-1 Signaling"],"prefix":"10.1093","volume":"194","author":[{"given":"Maximilian","family":"Larena","sequence":"first","affiliation":[{"name":"University of Gothenburg Vaccine Research Institute (GUVAX), Department of Microbiology and Immunology, University of Gothenburg , 405 30 \u00a0","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Holmgren","sequence":"additional","affiliation":[{"name":"University of Gothenburg Vaccine Research Institute (GUVAX), Department of Microbiology and Immunology, University of Gothenburg , 405 30 \u00a0","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Lebens","sequence":"additional","affiliation":[{"name":"University of Gothenburg Vaccine Research Institute (GUVAX), Department of Microbiology and Immunology, University of Gothenburg , 405 30 \u00a0","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Terrinoni","sequence":"additional","affiliation":[{"name":"University of Gothenburg Vaccine Research Institute (GUVAX), Department of Microbiology and Immunology, University of Gothenburg , 405 30 \u00a0","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Lundgren","sequence":"additional","affiliation":[{"name":"University of Gothenburg Vaccine Research Institute (GUVAX), Department of Microbiology and Immunology, University of Gothenburg , 405 30 \u00a0","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,4,15]]},"reference":[{"key":"2025030706040086500_r1","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1016\/j.vaccine.2004.11.010","article-title":"Mucosal adjuvants","volume":"23","author":"Freytag","year":"2005","journal-title":"Vaccine"},{"key":"2025030706040086500_r2","doi-asserted-by":"crossref","first-page":"50","DOI":"10.7774\/cevr.2012.1.1.50","article-title":"Mucosal vaccine adjuvants update","volume":"1","author":"Rhee","year":"2012","journal-title":"Clin Exp Vaccine Res"},{"key":"2025030706040086500_r3","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1038\/mi.2010.54","article-title":"Mucosal adjuvants and long-term memory development with special focus on CTA1-DD and other ADP-ribosylating toxins","volume":"3","author":"Lycke","year":"2010","journal-title":"Mucosal Immunol."},{"key":"2025030706040086500_r4","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1128\/CVI.00538-10","article-title":"Characterization of a mutant Escherichia coli heat-labile toxin, LT(R192G\/L211A), as a safe and effective oral adjuvant","volume":"18","author":"Norton","year":"2011","journal-title":"Clin. 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