Fas信号和TLR信号促进调节性树突状细胞负向调控CD4~+T细胞反应及相关机制研究
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摘要
本课题研究了Fas信号和TLR信号对调节性树突状细胞diffDC的调控作用和相关机制,并在此基础上研究了Fas信号和TLR信号刺激后的diffDC与T细胞相互调控的作用和意义。实验结果表明,来源于基质细胞ESSC的TGF-β通过活化ERK而促进了diffDC高表达Fas。Fas信号可促进diffDC高分泌IL-10和IP-10,其机制可能是通过ERK活化导致GSK-3失活从而上调β-catenin所介导。Fas信号也可促进diffDC高分泌IL-6,其机制可能是通过ERK活化诱导STAT3高度磷酸化有关。Fas/FasL信号参与了diffDC和活化型T细胞的相互作用后诱导diffDC更高分泌IL-10和IP-10,但是不参与diffDC更高分泌IL-6的过程。Fas信号还能够增强diffDC对于抗原特异性T细胞增殖的负向调节作用。diffDC在TLR激动剂刺激后可分泌更高水平的IP-10,其机制是由于TLR激动剂诱导diffDC分泌Ⅰ型干扰素(IFN-α/β),然后自分泌Ⅰ型干扰素促进了diffDC的IRF-3表达和STAT1磷酸化,最终导致TLR激动剂促进diffDC高分泌IP-10。进一步研究表明,diffDC通过高分泌IP-10选择性地趋化Th1细胞并抑制Th1细胞的增殖。由此,diffDC与活化型T细胞和Th1细胞通过多种方式相互调控,从而更好地联系固有免疫和适应性免疫,维持机体的稳态。
We report here the effects of Fas signal or TLR signal on the function of regulatory diffDCs and their reciprocal interaction with T cells. We investigated that induction of ERK activation by ESSC-derived TGF-6 is responsible for the high Fas expression of diffDCs derived from maDCs cocultured with ESSCs. Fas ligation induces preferential secretion of IL-10 and IP-10 by diffDCs though ERK-mediated inactivation of GSK-36 leading to the uprgulation of 6-catenin. Interestingly, diffDCs secrete high level of IL-6 through STAT3 activation mediated by ERK overactivation. Importantly, FasL-expressing the activated T cells can promote Fas-expressing diffDCs to secret more IL-10 and IP-10 via FasL/Fas interaction. Fas-ligated diffDCs could suppress maDC-initiated antigen-specific CD4 T cell proliferation more significantly. TLR agonists can promote diffDCs to secrete more IP-10 to attract Th1 cells and inhibit their proliferation via IRF3/IFN-6/STAT1 signaling. Our results provide the new manner for the negative regulation of T cell response by diffDCs, and maintenance of immune homeostaisis.
We report here the effects of Fas signal or TLR signal on the function of regulatory diffDCs and their reciprocal interaction with T cells. We investigated that induction of ERK activation by ESSC-derived TGF-6 is responsible for the high Fas expression of diffDCs derived from maDCs cocultured with ESSCs. Fas ligation induces preferential secretion of IL-10 and IP-10 by diffDCs though ERK-mediated inactivation of GSK-36 leading to the uprgulation of 6-catenin. Interestingly, diffDCs secrete high level of IL-6 through STAT3 activation mediated by ERK overactivation. Importantly, FasL-expressing the activated T cells can promote Fas-expressing diffDCs to secret more IL-10 and IP-10 via FasL/Fas interaction. Fas-ligated diffDCs could suppress maDC-initiated antigen-specific CD4 T cell proliferation more significantly. TLR agonists can promote diffDCs to secrete more IP-10 to attract Th1 cells and inhibit their proliferation via IRF3/IFN-6/STAT1 signaling. Our results provide the new manner for the negative regulation of T cell response by diffDCs, and maintenance of immune homeostaisis.
引文
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