TRIF-GEFH1-RhoB pathway is involved in MHCII expression on dendritic cells that is critical for CD4 T-cell activation
TRIF-GEFH1-RhoB pathway is involved in MHCII expression on dendritic cells that is critical for CD4 T-cell activation
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DOI：
10.1038/sj.emboj.7601286
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发表时间：
2006-09-06
期刊：
影响因子：
11.4
通讯作者：
Hirano, Toshio
中科院分区：
文献类型：
--
作者：
Kamon, Hokuto;Kawabe, Takaya;Hirano, Toshio
树突状细胞（DC）通过MHCII分子向CD4+ T细胞呈递抗原肽，在免疫应答中发挥核心作用。在这里，我们证明了TRIF-GEFH1-RhoB通路参与DC上MHCII表面的表达。我们发现TRIF（含TIR结构域的适配器诱导IFN β）-而不是髓系分化因子88 （MyD88）依赖的脂多糖（LPS）信号通路-在DC中对MHCII表面表达至关重要，随后是CD4+ t细胞激活。LPS增加RhoB的活性，但不增加RhoA、Cdc42或Rac1/2的活性，这种活性依赖于LPS- trif -信号通路，而不依赖于LPS- myd88信号通路。RhoB在DC中与MHCII+溶酶体共定位。DC中RhoB的显性阴性（DN）形式（DN-RhoB）或RhoB的RNAi抑制lps诱导的MHCII表面表达。此外，我们发现GEFH1与RhoB相关，DN-GEFH1或GEFH1的RNAi抑制lps介导的RhoB激活和MHCII表面表达。DN-RhoB减弱DC的CD4+ t细胞刺激活性。因此，我们的研究结果提供了一种在DC成熟阶段如何调节MHCII表面表达的分子机制。GEFH1-RhoB通过DC中脂多糖的trf依赖通路激活可能是控制CD4+ T细胞激活的关键靶点。
Dendritic cells (DC) play a central role in immune responses by presenting antigenic peptides to CD4+ T cells through MHCII molecules. Here, we demonstrate a TRIF-GEFH1-RhoB pathway is involved in MHCII surface expression on DC. We show the TRIF (TIR domain-containing adapter inducing IFN beta)- but not the myeloid differentiation factor 88 (MyD88)-dependent pathway of lipopolysaccharide (LPS)-signaling in DC is crucial for the MHCII surface expression, followed by CD4+ T-cell activation. LPS increased the activity of RhoB, but not of RhoA, Cdc42, or Rac1/2 in a manor dependent on LPS-TRIF- but not LPS-Myd88-signaling. RhoB colocalized with MHCII+ lysosomes in DC. A dominant-negative (DN) form of RhoB (DN-RhoB) or RhoB's RNAi in DC inhibited the LPS-induced MHCII surface expression. Moreover, we found GEFH1 associated with RhoB, and DN-GEFH1 or GEFH1's RNAi suppressed the LPS-mediated RhoB activation and MHCII surface expression. DN-RhoB attenuated the DC's CD4+ T-cell stimulatory activity. Thus, our results provide a molecular mechanism relating how the MHCII surface expression is regulated during the maturation stage of DC. The activation of GEFH1-RhoB through the TRIF-dependent pathway of LPS in DC might be a critical target for controlling the activation of CD4+ T cells.