Impaired intracellular calcium mobilization and NFATc1 availability in tolerant anti-insulin B cells
Impaired intracellular calcium mobilization and NFATc1 availability in tolerant anti-insulin B cells
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DOI：
10.4049/jimmunol.177.4.2234
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发表时间：
2006-08-15
影响因子：
4.4
通讯作者：
Thomas, James W.
中科院分区：
文献类型：
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作者：
Acevedo-Suarez, Carlos A.;Kilkenny, Dawn M.;Thomas, James W.
识别可溶性自身抗原的B淋巴细胞通常存在于处于功能失活或无反应性状态的正常个体中。目前的模型表明，这种耐受状态是通过与自身抗原的相互作用来维持的，所述自身抗原使BCR与下游信号传导途径解偶联并增加游离钙的水平。与此预期相反，携带抗胰岛素IG转基因（125 Tg）的B细胞维持在耐受状态，即使游离钙水平保持正常，酪氨酸激酶底物磷酸化在BCR刺激后也得以保留。在基础条件下，在125 Tg B细胞中，1，4，5-三磷酸肌醇的细胞内水平增加，NFATc 1水平降低。125 Tg B细胞在用离子霉素刺激后动员钙的能力明显受损，并且BCR诱导的来自内部储存的钙动员减少。相反，毒胡萝卜素中毒细胞内钙泵增加钙动员125 Tg B细胞。钙信号传导的变化伴随着125 Tg B细胞在抗IgM或离子霉素刺激后不能将NFATc 1转运到细胞核中。因此，BCR与多种信号通路的解离对于维持抗胰岛素125 Tg B细胞的耐受性不是必需的。相反，被自体胰岛素占据的BCR传递诱导细胞内钙动员变化的信号，并通过阻止关键转录因子如NFAT的激活来维持耐受性。
B lymphocytes that recognize soluble self-Ags are routinely found in normal individuals in a functionally inactive or anergic state. Current models indicate that this tolerant state is maintained by interactions with self-Ags that uncouple the BCR from downstream signaling pathways and increase levels of free calcium. Contrary to this expectation, B cells that harbor anti-insulin Ig transgenes (125Tg) are maintained in a tolerant state even though free calcium levels remain normal and tyrosine kinase substrate phosphorylation is preserved following BCR stimulation. Under basal conditions, intracellular levels of inositol 1,4,5-trisphosphate are increased and NFATc1 levels are reduced in 125Tg B cells. The 125Tg B cells are markedly impaired in their ability to mobilize calcium upon stimulation with ionomycin, and BCR-induced calcium mobilization from internal stores is decreased. In contrast, poisoning intracellular calcium pumps with thapsigargin increases calcium mobilization in 125Tg B cells. Changes in calcium signaling are accompanied by a failure of 125Tg B cells to translocate NFATc1 into the nucleus following stimulation with either anti-IgM or ionomycin. Thus, disassociation of BCR from multiple signaling pathways is not essential for maintaining tolerance in anti-insulin 125Tg B cells. Rather, BCRs that are occupied by autologous insulin deliver signals that induce changes in intracellular calcium mobilization and maintain tolerance by preventing activation of key transcription factors such as NFAT.