ß-catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8⺠T cells.
J Leukoc Biol
; 95(1): 179-90, 2014 Jan.
Article
em En
| MEDLINE
| ID: mdl-24023259
ABSTRACT
Whereas CD8⺠T cells are essential for anti-tumor immunity, tumors often evade CD8⺠T cell surveillance by immunosuppression. As the initiators of antigen-specific immune responses, DCs are likely to play a central role in regulating the balance between immunity and tolerance to tumor antigens and are specialized in their ability to cross-present exogenous tumor antigens on MHC class I molecules to initiate CD8⺠T cell immunity. However, it remains unclear whether and how tumors modulate DC functions to suppress CD8⺠T cell responses. We have shown previously that ß-catenin signaling in DCs promotes DC-mediated CD8⺠T cell tolerance. Here, we tested the hypothesis that ß-catenin in DCs mediates tumor-induced suppression of CD8⺠T cell immunity by inhibiting the ability of DCs in cross-priming. ß-Catenin was activated in DCs by multiple tumors in vivo and in vitro. B16 melanoma-bearing mice, when vaccinated with DC-targeting anti-DEC-205 mAb fused with tumor antigens, exhibited dampened CD8⺠immunity, similar to DC-ß-catenin(active) mice. DCs from DC-ß-catenin(active) and tumor-bearing mice were deficient in cross-priming, and antigen-specific CD8⺠T cells primed in these mice resulted in dampened CD8⺠memory responses. Importantly, DC-ß-cateninâ»/â» mice completely abrogate tumor-mediated inhibition of cross-priming, suggesting that tumor-induced inhibition of cross-priming is dependent on ß-catenin. Finally, enhancing cross-priming at the priming or recall phase rescued ß-catenin-suppressed CD8⺠immunity in DC-ß-catenin(active) and tumor-bearing mice. Thus, ß-catenin-mediated inhibition of cross-priming represents a new and potentially general mechanism that tumors employ to achieve immunosuppression.
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MEDLINE
Assunto principal:
Linfócitos T CD8-Positivos
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Apresentação Cruzada
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Beta Catenina
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Tolerância Imunológica
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Neoplasias
Limite:
Animals
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article