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Int. J. Mol. Sci. 2014, 15(4), 5508-5521; doi:10.3390/ijms15045508
Article

Transgene IL-6 Enhances DC-Stimulated CTL Responses by Counteracting CD4+25+Foxp3+ Regulatory T Cell Suppression via IL-6-Induced Foxp3 Downregulation

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Received: 24 December 2013; in revised form: 25 February 2014 / Accepted: 6 March 2014 / Published: 31 March 2014
(This article belongs to the Special Issue Mechanism of Action and Applications of Cytokines in Immunotherapy)
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Abstract: Dendritic cells (DCs), the most potent antigen-presenting cells have been extensively applied in clinical trials for evaluation of antitumor immunity. However, the efficacy of DC-mediated cancer vaccines is still limited as they are unable to sufficiently break the immune tolerance. In this study, we constructed a recombinant adenoviral vector (AdVIL-6) expressing IL-6, and generated IL-6 transgene-engineered DC vaccine (DCOVA/IL-6) by transfection of murine bone marrow-derived ovalbumin (OVA)-pulsed DCs (DCOVA) with AdVIL-6. We then assessed DCOVA/IL-6-stimulated cytotoxic T-lymphocyte (CTL) responses and antitumor immunity in OVA-specific animal tumor model. We demonstrate that DCOVA/IL-6 vaccine up-regulates expression of DC maturation markers, secretes transgene-encoded IL-6, and more efficiently stimulates OVA-specific CTL responses and therapeutic immunity against OVA-expressing B16 melanoma BL6-10OVA in vivo than the control DCOVA/Null vaccine. Moreover, DCOVA/IL-6-stimulated CTL responses were relatively maintained in mice with transfer of CD4+25+Foxp3+ Tr-cells, but significantly reduced when treated with anti-IL-6 antibody. In addition, we demonstrate that IL-6 down-regulates Foxp3-expression of CD4+25+Foxp3+ Tr-cells in vitro. Taken together, our results demonstrate that AdV-mediated IL-6 transgene-engineered DC vaccine stimulates potent CTL responses and antitumor immunity by counteracting CD4+25+ Tr immunosuppression via IL-6-induced Foxp3 down-regulation. Thus, IL-6 may be a good candidate for engineering DCs for cancer immunotherapy.
Keywords: dendritic cells (DCs); cytotoxic T lymphocytes (CTLs); interleukin-6 (IL-6); forkhead box P3 (Foxp3); antitumor immunity dendritic cells (DCs); cytotoxic T lymphocytes (CTLs); interleukin-6 (IL-6); forkhead box P3 (Foxp3); antitumor immunity
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Bhanumathy, K.K.; Zhang, B.; Ahmed, K.A.; Qureshi, M.; Xie, Y.; Tao, M.; Tan, X.; Xiang, J. Transgene IL-6 Enhances DC-Stimulated CTL Responses by Counteracting CD4+25+Foxp3+ Regulatory T Cell Suppression via IL-6-Induced Foxp3 Downregulation. Int. J. Mol. Sci. 2014, 15, 5508-5521.

AMA Style

Bhanumathy KK, Zhang B, Ahmed KA, Qureshi M, Xie Y, Tao M, Tan X, Xiang J. Transgene IL-6 Enhances DC-Stimulated CTL Responses by Counteracting CD4+25+Foxp3+ Regulatory T Cell Suppression via IL-6-Induced Foxp3 Downregulation. International Journal of Molecular Sciences. 2014; 15(4):5508-5521.

Chicago/Turabian Style

Bhanumathy, Kalpana K.; Zhang, Bei; Ahmed, Khawaja A.; Qureshi, Mabood; Xie, Yufeng; Tao, Min; Tan, Xin; Xiang, Jim. 2014. "Transgene IL-6 Enhances DC-Stimulated CTL Responses by Counteracting CD4+25+Foxp3+ Regulatory T Cell Suppression via IL-6-Induced Foxp3 Downregulation." Int. J. Mol. Sci. 15, no. 4: 5508-5521.



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