Gaur A, Yao X R, Scott D W
Division of Immunology and Immunotherapy, University of Rochester Cancer Center, NY 14642.
J Immunol. 1993 Mar 1;150(5):1663-9.
Previous studies in our laboratory demonstrated that overnight exposure of adult splenic B cells to anti-Ig resulted in an unresponsive state characterized by decreased antibody synthesis but normal mitogen-driven proliferation (i.e., energy). Because both anti-F(ab')2 and anti-mu were equally effective at inducing tolerance, it was important to determine whether cross-linking of IgD together with or separately from IgM influenced the induction of unresponsiveness. Although anti-mu induced significant unresponsiveness, treatment of adult splenic B cells with anti-delta alone generally failed to reduce the subsequent response to either LPS or fluoresceinated Brucella abortus. Interestingly, anti-delta synergized with suboptimal concentrations of anti-mu to induce tolerance. Synergy could be observed in this system when anti-delta was added either simultaneously with or before (but not after) anti-mu; moreover, anti-delta was effective in a pretreatment (wash-out) protocol. To investigate the role of protein tyrosine kinase (PTK) activity in tolerance induction, splenic B cells were treated with tyrphostin before treatment with either anti-mu or anti-delta. We found that pretreatment with tyrphostin for 2 h before the addition of anti-mu prevented the induction of unresponsiveness with this antibody, whereas this PTK inhibitor facilitated tolerance when used with anti-delta treatment only. We propose that cross-linking of surface IgM directly or indirectly invokes a tyrphostin-sensitive, PTK-dependent pathway leading to the early events in tolerance induction, which can be augmented under limiting conditions by anti-IgD. Because cross-linking of either receptor initiates several common pathways, simultaneous cross-linking can lead to synergy and a dominance of the IgM signal. In contrast, IgD alone may fail to elicit tolerance because this isotype may also be associated with different PTK that cause positive signaling.
我们实验室之前的研究表明，成年脾B细胞过夜暴露于抗Ig会导致一种无反应状态，其特征是抗体合成减少但丝裂原驱动的增殖（即活力）正常。由于抗F(ab')2和抗μ在诱导耐受方面同样有效，因此确定IgD与IgM一起或分别交联是否会影响无反应性的诱导很重要。尽管抗μ诱导了显著的无反应性，但单独用抗δ处理成年脾B细胞通常无法降低随后对LPS或荧光布鲁氏菌流产菌的反应。有趣的是，抗δ与次优浓度的抗μ协同作用以诱导耐受。当抗δ与抗μ同时添加或在抗μ之前（但不是之后）添加时，在该系统中可以观察到协同作用；此外，抗δ在预处理（洗脱）方案中有效。为了研究蛋白酪氨酸激酶（PTK）活性在耐受诱导中的作用，在用抗μ或抗δ处理之前，先用 tyrphostin处理脾B细胞。我们发现，在添加抗μ之前用tyrphostin预处理2小时可阻止该抗体诱导无反应性，而这种PTK抑制剂仅在与抗δ处理一起使用时促进耐受。我们提出，表面IgM的交联直接或间接引发了一条对tyrphostin敏感、依赖PTK的途径，导致耐受诱导的早期事件，在有限条件下可通过抗IgD增强。由于任何一种受体的交联都会启动几条共同途径，同时交联可导致协同作用和IgM信号的主导地位。相比之下，单独的IgD可能无法引发耐受，因为这种同种型也可能与导致正向信号传导的不同PTK相关。
