Rastelli Julia, Hömig-Hölzel Cornelia, Seagal Jane, Müller Werner, Hermann Andrea C, Rajewsky Klaus, Zimber-Strobl Ursula
Institute of Clinical Molecular Biology and Tumor Genetics, GSF-National Research Center for Environment and Health, Munich, Germany.
Blood. 2008 Feb 1;111(3):1448-55. doi: 10.1182/blood-2007-10-117655. Epub 2007 Nov 15.
The Epstein-Barr virus (EBV) protein LMP1 is considered to be a functional homologue of the CD40 receptor. However, in contrast to the latter, LMP1 is a constitutively active signaling molecule. To compare B cell-specific LMP1 and CD40 signaling in an unambiguous manner, we generated transgenic mice conditionally expressing a CD40/LMP1 fusion protein, which retained the LMP1 cytoplasmic tail but has lost the constitutive activity of LMP1 and needs to be activated by the CD40 ligand. We show that LMP1 signaling can completely substitute CD40 signaling in B cells, leading to normal B-cell development, activation, and immune responses including class-switch recombination, germinal center formation, and somatic hypermutation. In addition, the LMP1-signaling domain has a unique property in that it can induce class-switch recombination to IgG1 independent of cytokines. Thus, our data indicate that LMP1 has evolved to imitate T-helper cell function allowing activation, proliferation, and differentiation of EBV-infected B cells independent of T cells.
爱泼斯坦-巴尔病毒（EBV）蛋白LMP1被认为是CD40受体的功能同源物。然而，与后者不同的是，LMP1是一种组成型活性信号分子。为了以明确的方式比较B细胞特异性LMP1和CD40信号传导，我们构建了条件性表达CD40/LMP1融合蛋白的转基因小鼠，该融合蛋白保留了LMP1的细胞质尾巴，但失去了LMP1的组成型活性，需要由CD40配体激活。我们发现，LMP1信号传导可以完全替代B细胞中的CD40信号传导，导致正常的B细胞发育、激活和免疫反应，包括类别转换重组、生发中心形成和体细胞超突变。此外，LMP1信号结构域具有独特的特性，即它可以独立于细胞因子诱导向IgG1的类别转换重组。因此，我们的数据表明，LMP1已经进化到模仿辅助性T细胞的功能，从而使EBV感染的B细胞能够独立于T细胞进行激活、增殖和分化。
