1. Caveolin-1-Mediated Negative Signaling Plays a Critical Role in the Induction of Regulatory Dendritic Cells by DNA and Protein Coimmunization.
- Author
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Jinyao Li, Shuang Geng, Xiaoping Xie, Hu Liu, Guoxing Zheng, Xiaolin Sun, Gan Zhao, Ying Wan, Yuzhang Wu, Xuan Chen, Yiwei Zhong, and Bin Wang
- Subjects
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CAVEOLINS , *CELLULAR signal transduction , *DENDRITIC cells , *CELLULAR control mechanisms , *AUTOIMMUNE disease treatment , *T cells , *DNA , *INTERLEUKIN-10 - Abstract
Induction of Ag-speciflc regulatory T cells (iTregs) by vaccination is a promising strategy for treating autoimmune diseases. We previously demonstrated that DNA and protein covaccination converted naive T cells to Ag-speciflc iTregs by inducing CD11c+ CD40lowIL-10+ regulatory dendritic cells (DCregs). However, it is unclear how coimmunization induces the DCregs. In this paper, we report that the event is initiated by coentry of sequence-matched DNA and protein immunogens into the same DC via caveolae-mediated endocytosis, which leads to inhibition of phosphorylation of caveolin-1 (Cav-1), the main component of caveolae, and upregulation of Tollip. This triggers downstream signaling that upregulates suppressor of cytokine signaling 1 and downregulates NF-kB and STAT-l&agr;. Silencing either Cav-1 or Tollip blocks the negative signaling, leading to upregulated expression of CD40, downregulated production of IL-10, and loss of iTreg-inducing function. We further show that DCregs can be induced in culture from primary DCs and JAWS II DC lines by feeding them sequence-matched DNA and protein immunogens. The in vitro-generated DCregs are effective in ameliorating autoimmune and inflammatory diseases in several mouse models. Our study thus suggests that DNA and protein coimmunization induces DCregs through Cav-1- and Tollip-mediated negative signaling. It also describes a novel method for generating therapeutic DCregs in vitro. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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