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| Item Type: | Article |
|---|---|
| Title: | Prostaglandin E(2) in a TLR3- and 7/8-agonist-based DC maturation cocktail generates mature, cytokine-producing, migratory DCs but impairs antigen cross-presentation to CD8(+) T cells |
| Creators Name: | Gierlich, P., Lex, V., Technau, A., Keupp, A., Morper, L., Glunz, A., Sennholz, H., Rachor, J., Sauer, S., Marcu, A., Grigoleit, G.U., Wölfl, M., Schlegel, P.G. and Eyrich, M. |
| Abstract: | Mature dendritic cells (DCs) represent cellular adjuvants for optimal antigen presentation in cancer vaccines. Recently, a combination of prostaglandin E(2) (PGE(2)) with Toll-like receptor agonists (TLR-P) was proposed as a new standard to generate superior cytokine-producing DCs with high migratory capacity. Here, we compare TLR-P DCs with conventional DCs matured only with the proinflammatory cytokines TNFα and IL-1ß (CDCs), focussing on the interaction of resulting DCs with CD8(+) T-cells. TLR-P matured DCs showed elevated expression of activation markers such as CD80 and CD83 compared to CDCs, together with a significantly higher migration capacity. Secretion of IL-6, IL-8, IL-10, and IL-12 was highest after 16 h in TLR-P DCs, and only TLR-P DCs secreted active IL-12p70. TLR-P DCs as well as CDCs successfully primed multifunctional CD8(+) T-cells from naïve precursors specific for the peptide antigens Melan-A, NLGN4X, and PTP with comparable priming efficacy and T-cell receptor avidity. CD8(+) T-cells primed by TLR-P DCs showed significantly elevated expression of the integrin VLA-4 and a trend for higher T-cell numbers after expansion. In contrast, TLR-P DCs displayed a substantially reduced capability to cross-present CMVpp65 protein antigen to pp65-specific T cells, an effect that was dose-dependent on PGE(2) during DC maturation and reproducible with several responder T-cell lines. In conclusion, TLR-P matured DCs might be optimal presenters of antigens not requiring processing such as short peptides. However, PGE(2) seems less favorable for maturation of DCs intended to process and cross-present more complex vaccine antigens such as lysates, proteins or long peptides. |
| Keywords: | Dendritic Cells, Cancer Vaccines, Prostaglandin E(2), TLR Agonists, Tumor-Specific CD8(+) T Cells |
| Source: | Cancer Immunology Immunotherapy |
| ISSN: | 0340-7004 |
| Publisher: | Springer |
| Volume: | 69 |
| Number: | 6 |
| Page Range: | 1029-1042 |
| Date: | June 2020 |
| Official Publication: | https://doi.org/10.1007/s00262-019-02470-1 |
| PubMed: | View item in PubMed |
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