| First Author | Fu C | Year | 2015 |
| Journal | Proc Natl Acad Sci U S A | Volume | 112 |
| Issue | 9 | Pages | 2823-8 |
| PubMed ID | 25730849 | Mgi Jnum | J:220320 |
| Mgi Id | MGI:5634217 | Doi | 10.1073/pnas.1414167112 |
| Citation | Fu C, et al. (2015) beta-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+ T cells through regulation of IL-10. Proc Natl Acad Sci U S A 112(9):2823-8 |
| abstractText | Recent studies have demonstrated that beta-catenin in DCs serves as a key mediator in promoting both CD4(+) and CD8(+) T-cell tolerance, although how beta-catenin exerts its functions remains incompletely understood. Here we report that activation of beta-catenin in DCs inhibits cross-priming of CD8(+) T cells by up-regulating mTOR-dependent IL-10, suggesting blocking beta-catenin/mTOR/IL-10 signaling as a viable approach to augment CD8(+) T-cell immunity. However, vaccination of DC-beta-catenin(-/-) (CD11c-specific deletion of beta-catenin) mice surprisingly failed to protect them against tumor challenge. Further studies revealed that DC-beta-catenin(-/-) mice were deficient in generating CD8(+) T-cell immunity despite normal clonal expansion, likely due to impaired IL-10 production by beta-catenin(-/-) DCs. Deletion of beta-catenin in DCs or blocking IL-10 after clonal expansion similarly led to reduced CD8(+) T cells, suggesting that beta-catenin in DCs plays a positive role in CD8(+) T-cell maintenance postclonal expansion through IL-10. Thus, our study has not only identified mTOR/IL-10 as a previously unidentified mechanism for beta-catenin-dependent inhibition of cross-priming, but also uncovered an unexpected positive role that beta-catenin plays in maintenance of CD8(+) T cells. Despite beta-catenin's opposite functions in regulating CD8(+) T-cell responses, selectively blocking beta-catenin with a pharmacological inhibitor during priming phase augmented DC vaccine-induced CD8(+) T-cell immunity and improved antitumor efficacy, suggesting manipulating beta-catenin signaling as a feasible therapeutic strategy to improve DC vaccine efficacy. |
