β-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+ T cells through regulation of IL-10.
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.
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;
Chunmei
C
Fu
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;
Xinjun
X
Liang
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53213;
Weiguo
W
Cui
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
Julia L
JL
Ober-Blöbaum
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;
Joseph
J
Vazzana
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263; Department of Research, Mayo Clinic in Arizona, Scottsdale, AZ 85259; and.
Protul A
PA
Shrikant
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;
Kelvin P
KP
Lee
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
Björn E
http://orcid.org/0000-0002-2484-7842
BE
Clausen
Research Oncology, Genentech, South San Francisco, CA 94080.
Ira
I
Mellman
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263; aiminjia@buffalo.edu.
Aimin
A
Jiang
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019496:Cancer Vaccines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D007111:Immunity, Cellular; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D051176:beta Catenin / Q000235:genetics / Q000276:immunology*
D019496:Cancer Vaccines; C556062:IL10 protein, mouse; D051176:beta Catenin; D016753:Interleukin-10; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
CD8+ T-cell immunity; IL-10; beta-catenin; dendritic cells; mTOR