Differential Adjuvant Activities of TLR7 and TLR9 Agonists Inversely Correlate with Nitric Oxide and PGE2 Production
UMass Chan Affiliations
Department of MedicineDocument Type
Journal ArticlePublication Date
2015-04-13
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Activation of different pattern recognition receptors causes distinct profiles of innate immune responses, which in turn dictate the adaptive immune response. We found that mice had higher CD4+ T cell expansion to an immunogen, ovalbumin, when coadministered with CpG than with CL097 in vivo. To account for this differential adjuvanticity, we assessed the activities of CpG and CL097 on antigen-specific CD4+ T cell expansion in vitro using an OT-II CD4+ T cell/bone marrow-derived dendritic cell (DC) co-culture system. Unexpectedly, ovalbumin-stimulated expansion of OT-II CD4+ T cells in vitro was potently suppressed by both TLR agonists, with CL097 being stronger than CpG. The suppression was synergistically reversed by co-inhibition of cyclooxygenases 1 and 2, and inducible nitric oxide (NO) synthase. In addition, stimulation of OT-II CD4+ T cell/DC cultures with CL097 induced higher levels of CD4+ T cell death than stimulation with CpG, and this CD4+ T cell turnover was reversed by NO and PGE2 inhibition. Consistently, the co-cultures stimulated with CL097 produced higher levels of prostaglandin E2 (PGE2) and NO than stimulation with CpG. CL097 induced higher PGE2 production in DC cultures and higher IFN-gamma in the OT-II CD4+ T cell/DC cultures, accounting for the high levels of PGE2 and NO. This study demonstrates that the adjuvant activities of immunostimulatory molecules may be determined by differential induction of negative regulators, including NO and PGE2 suppressing clonal expansion and promoting cell death of CD4+ T cells.Source
PLoS One. 2015 Apr 13;10(4):e0123165. doi: 10.1371/journal.pone.0123165. eCollection 2015.. Link to article on publisher's siteDOI
10.1371/journal.pone.0123165Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39698PubMed ID
25875128Related Resources
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This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
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10.1371/journal.pone.0123165
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Except where otherwise noted, this item's license is described as <p>This is an open access article distributed under the terms of the <a href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</a>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited</p>