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  • 标题:Silencing RORγt in Human CD4+ T cells with CD30 aptamer-RORγt shRNA Chimera
  • 本地全文:下载
  • 作者:Xiaofei Shi ; Pingfang Song ; Shao Tao
  • 期刊名称:Scientific Reports
  • 电子版ISSN:2045-2322
  • 出版年度:2019
  • 卷号:9
  • 期号:1
  • 页码:1-9
  • DOI:10.1038/s41598-019-46855-9
  • 出版社:Springer Nature
  • 摘要:Targeting specific T cell subtypes and intervening in their function are emerging a critical strategy for treatment of autoimmune diseases. Here we report that an RNA CD30 aptamer was utilized to deliver short hairpin RNA (shRNA) to CD30 + T cells to target retinoic acid receptor-related orphan receptor gamma t (RORγt), leading to impaired expression of RORγt and suppression of IL-17A and IL-17F. A DNA template consisting of CD30 aptamer and RORγt shRNA sequences was synthesized and was transcribed CD30 aptamer-RORγt shRNA chimera (CD30-AshR-RORγt). Insertion of 2'-F-dCTP and 2'-FdUTP was incorporated during CD30-AshR-RORγt transcription to increase its resistance to RNase. CD30-AshR-RORγt was specifically up-taken by CD30 + Karpas 299 cells, but not by Jurkat cells which lack CD30. It was also up-taken by activated, CD30 expressing human CD4 + T cells, but not by resting CD4 + T cells. The RORγt shRNA moiety of CD30-AshR-RORγt chimera was cleaved and released by Dicers. Then, CD30-AshR-RORγt suppressed RORγt gene expression in Karpas 299 cells and activated human CD4 + T cells. Consistently, silence of Th17 cell differentiation and IL-17A and IL-17F synthesis with CD30-AshR-RORγt was demonstrated in activated human CD4 + T cells from healthy donors and RA patients. CD30-AshR-negative control chimera and prostate specific membrane antigen (PSMA)-AshR-RORγt had no significant impact on the expression of RORγt or IL-17A and IL-17F. These data present a novel strategy for shRNA delivery using CD30 RNA aptamers to down-regulate CD30 + Th17 cells and can be developed as a targeted therapy for treating Th17 cell mediated conditions.
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