ß-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, 2015 Mar 03.
Article
in En
| MEDLINE
| ID: mdl-25730849
ABSTRACT
Recent studies have demonstrated that ß-catenin in DCs serves as a key mediator in promoting both CD4(+) and CD8(+) T-cell tolerance, although how ß-catenin exerts its functions remains incompletely understood. Here we report that activation of ß-catenin in DCs inhibits cross-priming of CD8(+) T cells by up-regulating mTOR-dependent IL-10, suggesting blocking ß-catenin/mTOR/IL-10 signaling as a viable approach to augment CD8(+) T-cell immunity. However, vaccination of DC-ß-catenin(-/-) (CD11c-specific deletion of ß-catenin) mice surprisingly failed to protect them against tumor challenge. Further studies revealed that DC-ß-catenin(-/-) mice were deficient in generating CD8(+) T-cell immunity despite normal clonal expansion, likely due to impaired IL-10 production by ß-catenin(-/-) DCs. Deletion of ß-catenin in DCs or blocking IL-10 after clonal expansion similarly led to reduced CD8(+) T cells, suggesting that ß-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 ß-catenin-dependent inhibition of cross-priming, but also uncovered an unexpected positive role that ß-catenin plays in maintenance of CD8(+) T cells. Despite ß-catenin's opposite functions in regulating CD8(+) T-cell responses, selectively blocking ß-catenin with a pharmacological inhibitor during priming phase augmented DC vaccine-induced CD8(+) T-cell immunity and improved antitumor efficacy, suggesting manipulating ß-catenin signaling as a feasible therapeutic strategy to improve DC vaccine efficacy.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Dendritic Cells
/
Interleukin-10
/
CD8-Positive T-Lymphocytes
/
Beta Catenin
/
Immunity, Cellular
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Year:
2015
Type:
Article