Jeannin P, Delneste Y, Lecoanet-Henchoz S, Gauchat J F, Ellis J, Bonnefoy J Y
Geneva Biomedical Research Institute, GlaxoWellcome Research and Development, Immunology Department, 14, Chemin des Aulx, CH-1228 Plan les Ouates, Geneva, Switzerland.
J Biol Chem. 1997 Jun 20;272(25):15613-9. doi: 10.1074/jbc.272.25.15613.
Immunoglobulin (Ig) E production by B cells requires two primary signals provided by T cells, interleukin (IL)-4 or IL-13 and CD40 ligand (CD40L). In addition, costimulatory signals, such as CD23-CD21 interaction, contribute further ensuring a selective control over this production. Recently, CD28, expressed on T cells, has been reported to be involved in this process. The CD28 ligands, CD80 (B7-1) and CD86 (B7-2), are expressed on human tonsillar B cells, and their expression is up-regulated by IL-4, IL-13, and/or an anti-CD40 monoclonal antibody (mAb). We have investigated whether signaling via the B7 molecules affects IgE synthesis. Human B cells were stimulated by IL-4 plus anti-CD40 mAb in the presence of different anti-B7 mAbs. Cross-linking of CD86 with IT2.2 potentiated IgE and IgG4 production and epsilon transcripts expression. The production of the other isotypes was not modulated. Conversely, the anti-CD80 and the other anti-CD86 mAbs tested had no effect. The increase of IgE and IgG4 production induced by IT2.2 was accompanied by an increase in proliferation, in cell surface density of CD23, and in CD23 binding to CD21-expressing B cells. In contrast, the expression of other B cell surface molecules such as CD11a, CD30, and CD58 remained unaffected. Since IT2.2 favors CD23-CD21 pairing, we tested whether blocking this interaction affected IT2.2-increased IgE production. The neutralizing anti-CD23 mAb, Mab 25, caused a dose-dependent inhibition of the effect of IT2.2 on IgE synthesis. Finally, IT2.2 potentiation on B cell proliferation and IgE production required the two primary signals, IL-4 and anti-CD40 mAb, since IT2.2 alone or in combination with only one of these stimuli did not show any effect on B cells. This study is the first demonstration of a signaling role for CD86. Together with IL-4 or IL-13 and CD40L, CD86 favors CD23-CD21 pairing and consequently functions as a selective and potent costimulus for human IgE and IgG4 synthesis.
B细胞产生免疫球蛋白（Ig）E需要T细胞提供的两个主要信号，即白细胞介素（IL）-4或IL-13以及CD40配体（CD40L）。此外，共刺激信号，如CD23-CD21相互作用，进一步有助于确保对这种产生进行选择性控制。最近，据报道T细胞上表达的CD28参与了这一过程。CD28配体CD80（B7-1）和CD86（B7-2）在人扁桃体B细胞上表达，并且它们的表达被IL-4、IL-13和/或抗CD40单克隆抗体（mAb）上调。我们研究了通过B7分子的信号传导是否影响IgE合成。在不同的抗B7 mAb存在的情况下，用IL-4加抗CD40 mAb刺激人B细胞。用IT2.2使CD86交联可增强IgE和IgG4的产生以及ε转录本的表达。其他同种型的产生未受调节。相反，所测试的抗CD80和其他抗CD86 mAb没有作用。IT2.2诱导的IgE和IgG4产生的增加伴随着增殖、CD23细胞表面密度以及CD23与表达CD21的B细胞结合的增加。相比之下，其他B细胞表面分子如CD11a、CD30和CD58的表达未受影响。由于IT2.2有利于CD23-CD21配对，我们测试了阻断这种相互作用是否会影响IT2.2增加的IgE产生。中和性抗CD23 mAb Mab 25对IT2.2对IgE合成的作用产生剂量依赖性抑制。最后，IT2.2对B细胞增殖和IgE产生的增强作用需要IL-4和抗CD40 mAb这两个主要信号，因为单独的IT2.2或与这些刺激之一组合都未对B细胞显示任何作用。这项研究首次证明了CD86的信号传导作用。与IL-4或IL-13以及CD40L一起，CD86有利于CD23-CD21配对，因此作为人IgE和IgG4合成的选择性和强效共刺激因子发挥作用。
