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Attenuated Expression of A20 Markedly Increases the Efficacy of Double-Stranded RNA-Activated Dendritic Cells As an Anti-Cancer Vaccine

(2009) JOURNAL OF IMMUNOLOGY. 182(2). p.860-870
Author
Organization
Abstract
A20 is a zinc finger protein with ubiquitin-modifying activity. A20 has been described as negatively regulating signaling induced by the TNF receptor and TLR family in a number of cell types, including mouse bone marrow-derived dendritic cells (DiCs). However, the expression and effect of A20 in activated human monocyte-derived DCs have not been previously evaluated. We report that DCs activated with the TLR3 ligand poly(I:C) up-regulate A20. Down-regulating A20 demonstrated its role in the functional activation of DCs. A20 down-regulated DCs showed higher activation of the transcription factors NF-kappa B and activator protein-1, which resulted in increased and sustained production of IL-6, IL-10, and IL-12p70. We additionally silenced the immunosuppressive cytokine IL-10 and demonstrated that IL-10 inhibits T cell proliferation. We further demonstrated that A20 down-regulated DCs skew naive CD4(+) T cells toward IFN-gamma producing Th1 cells, a process which is dependent on IL-12p70 and which is unaffected by IL-10. Furthermore, A20 and/or IL-10 down-regulated DCs had an enhanced capacity to prime Melan-A/MART-1 specific CD8(+) T cells. Finally, we demonstrated that potent T cell stimulatory DCs are generated by the simultaneous delivery of poly(I:C12U), A20, or A20/IL-10 small interfering RNA and Ag-encoding mRNA, introducing a one step approach to improve DC-based vaccines. Together these findings demonstrate that A20 negatively regulates NF-kappa B and activator protein-1 in DCs and that down-regulation of A20 results in DCs with enhanced T cell stimulatory capacity.

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Citation

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MLA
Breckpot, Karine et al. “Attenuated Expression of A20 Markedly Increases the Efficacy of Double-Stranded RNA-Activated Dendritic Cells As an Anti-Cancer Vaccine.” JOURNAL OF IMMUNOLOGY 182.2 (2009): 860–870. Print.
APA
Breckpot, K., Aerts-Toegaert, C., Heirman, C., Peeters, U., Beyaert, R., Aerts, J. L., & Thielemans, K. (2009). Attenuated Expression of A20 Markedly Increases the Efficacy of Double-Stranded RNA-Activated Dendritic Cells As an Anti-Cancer Vaccine. JOURNAL OF IMMUNOLOGY, 182(2), 860–870.
Chicago author-date
Breckpot, Karine, Cindy Aerts-Toegaert, Carlo Heirman, Uschi Peeters, Rudi Beyaert, Joeri L Aerts, and Kris Thielemans. 2009. “Attenuated Expression of A20 Markedly Increases the Efficacy of Double-Stranded RNA-Activated Dendritic Cells As an Anti-Cancer Vaccine.” Journal of Immunology 182 (2): 860–870.
Chicago author-date (all authors)
Breckpot, Karine, Cindy Aerts-Toegaert, Carlo Heirman, Uschi Peeters, Rudi Beyaert, Joeri L Aerts, and Kris Thielemans. 2009. “Attenuated Expression of A20 Markedly Increases the Efficacy of Double-Stranded RNA-Activated Dendritic Cells As an Anti-Cancer Vaccine.” Journal of Immunology 182 (2): 860–870.
Vancouver
1.
Breckpot K, Aerts-Toegaert C, Heirman C, Peeters U, Beyaert R, Aerts JL, et al. Attenuated Expression of A20 Markedly Increases the Efficacy of Double-Stranded RNA-Activated Dendritic Cells As an Anti-Cancer Vaccine. JOURNAL OF IMMUNOLOGY. 2009;182(2):860–70.
IEEE
[1]
K. Breckpot et al., “Attenuated Expression of A20 Markedly Increases the Efficacy of Double-Stranded RNA-Activated Dendritic Cells As an Anti-Cancer Vaccine,” JOURNAL OF IMMUNOLOGY, vol. 182, no. 2, pp. 860–870, 2009.
@article{595645,
  abstract     = {A20 is a zinc finger protein with ubiquitin-modifying activity. A20 has been described as negatively regulating signaling induced by the TNF receptor and TLR family in a number of cell types, including mouse bone marrow-derived dendritic cells (DiCs). However, the expression and effect of A20 in activated human monocyte-derived DCs have not been previously evaluated. We report that DCs activated with the TLR3 ligand poly(I:C) up-regulate A20. Down-regulating A20 demonstrated its role in the functional activation of DCs. A20 down-regulated DCs showed higher activation of the transcription factors NF-kappa B and activator protein-1, which resulted in increased and sustained production of IL-6, IL-10, and IL-12p70. We additionally silenced the immunosuppressive cytokine IL-10 and demonstrated that IL-10 inhibits T cell proliferation. We further demonstrated that A20 down-regulated DCs skew naive CD4(+) T cells toward IFN-gamma producing Th1 cells, a process which is dependent on IL-12p70 and which is unaffected by IL-10. Furthermore, A20 and/or IL-10 down-regulated DCs had an enhanced capacity to prime Melan-A/MART-1 specific CD8(+) T cells. Finally, we demonstrated that potent T cell stimulatory DCs are generated by the simultaneous delivery of poly(I:C12U), A20, or A20/IL-10 small interfering RNA and Ag-encoding mRNA, introducing a one step approach to improve DC-based vaccines. Together these findings demonstrate that A20 negatively regulates NF-kappa B and activator protein-1 in DCs and that down-regulation of A20 results in DCs with enhanced T cell stimulatory capacity.},
  author       = {Breckpot, Karine and Aerts-Toegaert, Cindy and Heirman, Carlo and Peeters, Uschi and Beyaert, Rudi and Aerts, Joeri L and Thielemans, Kris},
  issn         = {0022-1767},
  journal      = {JOURNAL OF IMMUNOLOGY},
  language     = {eng},
  number       = {2},
  pages        = {860--870},
  title        = {Attenuated Expression of A20 Markedly Increases the Efficacy of Double-Stranded RNA-Activated Dendritic Cells As an Anti-Cancer Vaccine},
  volume       = {182},
  year         = {2009},
}

Web of Science
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