Attenuated Expression of A20 Markedly Increases the Efficacy of Double-Stranded RNA-Activated Dendritic Cells As an Anti-Cancer Vaccine
Attenuated Expression of A20 Markedly Increases the Efficacy of Double-Stranded RNA-Activated Dendritic Cells As an Anti-Cancer Vaccine
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DOI：
10.4049/jimmunol.182.2.860
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发表时间：
2009-01-15
影响因子：
4.4
通讯作者：
Thielemans, Kris
中科院分区：
文献类型：
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作者：
Breckpot, Karine;Aerts-Toegaert, Cindy;Thielemans, Kris
A20是一种具有泛素修饰活性的锌指蛋白。A20已被描述为在许多细胞类型中负调控TNF受体和TLR家族诱导的信号传导，包括小鼠骨髓源性树突状细胞（DiCs）。然而，A20在活化的人单核细胞来源的dc中的表达和作用尚未被评估。我们报道了被TLR3配体poly（I:C）激活的dc上调A20。A20的下调表明其在DCs功能激活中的作用。A20下调的dc表现出更高的转录因子NF-kappa B和激活蛋白1的激活，导致IL-6、IL-10和IL-12p70的持续增加。我们还沉默了免疫抑制细胞因子IL-10，并证明IL-10抑制T细胞增殖。我们进一步证明，A20下调的dc使初始CD4(+) T细胞向产生ifn - γ的Th1细胞倾斜，这一过程依赖于IL-12p70，不受IL-10的影响。此外，A20和/或IL-10下调的dc具有增强的启动Melan-A/MART-1特异性CD8(+) T细胞的能力。最后，我们证明了通过同时递送poly（I:C12U）、A20或A20/IL-10小干扰RNA和ag编码mRNA，可以产生有效的T细胞刺激dc，从而引入了一种一步法来改进dc疫苗。这些发现表明，A20负调控dc中的NF-kappa B和激活蛋白-1，A20的下调导致dc具有增强的T细胞刺激能力。免疫学杂志，2009,18(2):860-870。
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. The Journal of Immunology, 2009, 182: 860-870.