Immunoglobulin signal transduction guides the specificity of B cell-T cell interactions and is blocked in tolerant self-reactive B cells.
Immunoglobulin signal transduction guides the specificity of B cell-T cell interactions and is blocked in tolerant self-reactive B cells.
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DOI：
10.1084/jem.179.2.425
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发表时间：
1994-02-01
期刊：
影响因子：
--
通讯作者：
Goodnow CC
中科院分区：
文献类型：
--
作者：
Cooke MP;Heath AW;Shokat KM;Zeng Y;Finkelman FD;Linsley PS;Howard M;Goodnow CC
抗体（Ab）应答的特异性取决于将辅助性T（Th）淋巴细胞信号集中到能够结合外源抗原（Ag）的合适的B淋巴细胞，而远离非特异性或自身反应性B细胞。为了研究阻止自身反应性B淋巴细胞活化的分子机制，将从免疫球蛋白（IG）转基因小鼠中获得的对Ag鸡蛋溶菌酶（HEL）特异的B细胞的活化要求与从Ig转基因小鼠中分离的功能耐受性B细胞的活化要求进行比较，所述Ig转基因小鼠也表达可溶性HEL。为了消除对表面IG介导的Ag摄取和呈递的需要，并允许单独研究sIG信号传导的作用，我们评估了来自bm 12品系小鼠的同种异体T细胞为C57 BL/6品系转基因B细胞提供体内帮助的能力。有趣的是，非耐受性IG转基因B细胞需要同种异体Th细胞和可溶性HEL的结合以有效活化和Ab产生。相比之下，来自IG/HEL双转基因小鼠的耐受性自身反应性B细胞对同种异体T细胞和可溶性HEL的相同组合反应较差。然而，耐受性B细胞在体外对白细胞介素4和抗CD 40抗体的刺激反应正常，这表明它们保留了对T细胞辅助介质的反应能力。然而，耐受性B细胞在sIg信号传导途径中表现出近端阻断，其阻止响应于可溶性HEL的结合的受体相关酪氨酸激酶的活化。通过使用能够在耐受性B细胞中触发sIg信号传导的更有效的膜结合形式的HEL，证实了这种sIg信号传导缺陷的功能意义，这显著恢复了它们与同种异体Th细胞合作并产生Ab的能力。这些发现表明，Ag特异性B细胞需要两个信号来安装T细胞依赖性Ab反应，并确定调节sIg信号传导作为控制自身反应性B细胞的机制。
The specificity of antibody (Ab) responses depends on focusing helper T (Th) lymphocyte signals to suitable B lymphocytes capable of binding foreign antigens (Ags), and away from nonspecific or self-reactive B cells. To investigate the molecular mechanisms that prevent the activation of self-reactive B lymphocytes, the activation requirements of B cells specific for the Ag hen egg lysozyme (HEL) obtained from immunoglobulin (Ig)-transgenic mice were compared with those of functionally tolerant B cells isolated from Ig-transgenic mice which also express soluble HEL. To eliminate the need for surface (s)Ig- mediated Ag uptake and presentation and allow the effects of sIg signaling to be studied in isolation, we assessed the ability of allogeneic T cells from bm12 strain mice to provide in vivo help to C57BL/6 strain-transgenic B cells. Interestingly, non-tolerant Ig- transgenic B cells required both allogeneic Th cells and binding of soluble HEL for efficient activation and Ab production. By contrast, tolerant self-reactive B cells from Ig/HEL double transgenic mice responded poorly to the same combination of allogeneic T cells and soluble HEL. The tolerant B cells were nevertheless normally responsive to stimulation with interleukin 4 and anti-CD40 Abs in vitro, suggesting that they retained the capacity to respond to mediators of T cell help. However, the tolerant B cells exhibited a proximal block in the sIg signaling pathway which prevented activation of receptor- associated tyrosine kinases in response to the binding of soluble HEL. The functional significance of this sIg signaling defect was confirmed by using a more potent membrane-bound form of HEL capable of triggering sIg signaling in tolerant B cells, which markedly restored their ability to collaborate with allogeneic Th cells and produce Ab. These findings indicate that Ag-specific B cells require two signals for mounting a T cell-dependent Ab response and identify regulation of sIg signaling as a mechanism for controlling self-reactive B cells.