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Attenuated expression of A20 markedly increases the efficacy of double-stranded RNA-activated dendritic cells as an anti-cancer vaccine.

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 (DCs). 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-kappaB 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-kappaB and activator protein-1 in DCs and that down-regulation of A20 results in DCs with enhanced T cell stimulatory capacity.
AuthorsKarine Breckpot, Cindy Aerts-Toegaert, Carlo Heirman, Uschi Peeters, Rudi Beyaert, Joeri L Aerts, Kris Thielemans
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 182 Issue 2 Pg. 860-70 (Jan 15 2009) ISSN: 1550-6606 [Electronic] United States
PMID19124729 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Adjuvants, Immunologic
  • Cancer Vaccines
  • DNA-Binding Proteins
  • Interleukin-6
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Nuclear Proteins
  • RNA, Double-Stranded
  • RNA, Small Interfering
  • Transcription Factor AP-1
  • Interleukin-10
  • Interleukin-12
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3
Topics
  • Adjuvants, Immunologic (biosynthesis, genetics, physiology)
  • CD4-Positive T-Lymphocytes (immunology)
  • Cancer Vaccines (genetics, immunology)
  • Cells, Cultured
  • Coculture Techniques
  • DNA-Binding Proteins
  • Dendritic Cells (immunology, metabolism, transplantation)
  • Down-Regulation (genetics, immunology)
  • Humans
  • Interleukin-10 (biosynthesis)
  • Interleukin-12 (biosynthesis)
  • Interleukin-6 (biosynthesis)
  • Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, genetics)
  • Lymphocyte Activation (genetics, immunology)
  • Monocytes (immunology, metabolism)
  • NF-kappa B (antagonists & inhibitors, biosynthesis)
  • Nuclear Proteins (antagonists & inhibitors, biosynthesis, genetics)
  • RNA Interference (immunology)
  • RNA, Double-Stranded (physiology)
  • RNA, Small Interfering (physiology)
  • Transcription Factor AP-1 (antagonists & inhibitors, biosynthesis)
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Up-Regulation (genetics, immunology)

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