β-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+ T cells through regulation of IL-10

Chunmei Fu, Xinjun Liang, Weiguo Cui, Julia L. Ober-Blöbaum, Joseph Vazzana, Protul A. Shrikant, Kelvin P. Lee, Björn E. Clausen, Ira Mellman, Aimin Jiang

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Recent studies have demonstrated that β-catenin in DCs serves as a key mediator in promoting both CD4+ and CD8+ T-cell tolerance, although how β-catenin exerts its functions remains incompletely understood. Here we report that activation of β-catenin in DCs inhibits cross-priming of CD8+ T cells by up-regulating mTOR-dependent IL-10, suggesting blocking β-catenin/mTOR/IL-10 signaling as a viable approach to augment CD8+ T-cell immunity. However, vaccination of DC-β-catenin-/- (CD11c-specific deletion of β-catenin) mice surprisingly failed to protect them against tumor challenge. Further studies revealed that DC-β-catenin-/- mice were deficient in generating CD8+ T-cell immunity despite normal clonal expansion, likely due to impaired IL-10 production by β-catenin-/- DCs. Deletion of β-catenin in DCs or blocking IL-10 after clonal expansion similarly led to reduced CD8+ T cells, suggesting that β-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 β-catenin-dependent inhibition of cross-priming, but also uncovered an unexpected positive role that β-catenin plays in maintenance of CD8+ T cells. Despite β-catenin's opposite functions in regulating CD8+ T-cell responses, selectively blocking β-catenin with a pharmacological inhibitor during priming phase augmented DC vaccine-induced CD8+ T-cell immunity and improved antitumor efficacy, suggesting manipulating β-catenin signaling as a feasible therapeutic strategy to improve DC vaccine efficacy.

Original languageEnglish (US)
Pages (from-to)2823-2828
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number9
DOIs
StatePublished - Mar 3 2015
Externally publishedYes

Keywords

  • Beta-catenin
  • CD8 T-cell immunity
  • Dendritic cells
  • IL-10
  • MTOR

ASJC Scopus subject areas

  • General

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