Enforced Bcl-2 expression inhibits antigen-mediated clonal elimination of peripheral B cells in an antigen dose-dependent manner and promotes receptor editing in autoreactive, immature B cells.
Enforced Bcl-2 expression inhibits antigen-mediated clonal elimination of peripheral B cells in an antigen dose-dependent manner and promotes receptor editing in autoreactive, immature B cells.
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DOI：
10.1084/jem.186.9.1513
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发表时间：
1997-11-03
期刊：
影响因子：
--
通讯作者：
Nemazee D
中科院分区：
文献类型：
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作者：
Lang J;Arnold B;Hammerling G;Harris AW;Korsmeyer S;Russell D;Strasser A;Nemazee D
未成熟和成熟 B 细胞建立免疫耐受的机制似乎不同。膜结合自身抗原被认为会诱导未成熟 B 细胞发育停滞和受体编辑，而成熟 B 细胞在受到相同刺激时会缩短寿命。在本研究中，我们使用 Eμ–bcl-2-22 转基因 (Tg) 小鼠来测试这样的预测：在 B 细胞中强制表达 Bcl-2 凋亡抑制剂将拯救成熟但不成熟的 B 细胞免受耐受诱导。为了监测对天然膜自身抗原 H-2Kb 的耐受性，我们将 3–83μδ（抗 Kk,b）Ig Tg 小鼠与 H-2b 小鼠或外周表达转基因驱动的 Kb 的小鼠进行交配。在 3–83μδ/bcl-2 Tg 小鼠中，肝脏 (MT-Kb Tg) 或上皮细胞 (KerIV-Kb Tg) 中外周 Kb 抗原表达诱导的自身反应性 B 细胞缺失分别被部分或完全抑制。此外，Bcl-2 保护腹膜 B-2 B 细胞免受急性抗原暴露介导的缺失，但这种保护可以通过更高的抗原剂量来克服。与其阻断外周自身耐受的能力相反，Bcl-2 过表达未能抑制骨髓抗原表达诱导的中枢耐受，反而增强了受体编辑过程。这些研究表明细胞凋亡在中枢和外周 B 细胞耐受中发挥着不同的作用。
The mechanisms that establish immune tolerance in immature and mature B cells appear to be distinct. Membrane-bound autoantigen is thought to induce developmental arrest and receptor editing in immature B cells, whereas mature B cells have shortened lifespans when exposed to the same stimulus. In this study, we used Eμ–bcl-2-22 transgenic (Tg) mice to test the prediction that enforced expression of the Bcl-2 apoptotic inhibitor in B cells would rescue mature, but not immature, B cells from tolerance induction. To monitor tolerance to the natural membrane autoantigen H-2Kb, we bred 3–83μδ (anti-Kk,b) Ig Tg mice to H-2b mice or to mice expressing transgene-driven Kb in the periphery. In 3–83μδ/bcl-2 Tg mice, deletion of autoreactive B cells induced by peripheral Kb antigen expression in the liver (MT-Kb Tg) or epithelia (KerIV-Kb Tg), was partly or completely inhibited, respectively. Furthermore, Bcl-2 protected peritoneal B-2 B cells from deletion mediated by acute antigen exposure, but this protection could be overcome by higher antigen dose. In contrast to its ability to block peripheral self-tolerance, Bcl-2 overexpression failed to inhibit central tolerance induced by bone marrow antigen expression, but instead, enhanced the receptor editing process. These studies indicate that apoptosis plays distinct roles in central and peripheral B cell tolerance.