Klaus G G, Choi M S, Holman M
Laboratory of Cellular Immunology, National Institute for Medical Research, Mill Hill, London, GB.
Eur J Immunol. 1994 Dec;24(12):3229-32. doi: 10.1002/eji.1830241248.
The immunosuppressive drugs cyclosporine A (CsA) and FK506 selectively abrogate Ca(++)-regulated activation pathways in both T cells and B cells. We show here that anti-CD40-induced murine B cell proliferation, in the presence or absence of interleukin-4 (IL-4) is, like the response to anti-immunoglobulin (Ig), abrogated by 1-5 ng/ml (concentration causing 50% inhibition ca. 1 nM) FK506. However, the effects of the drug on proliferative responses elicited by anti-Ig or anti-CD40 differ significantly: firstly, the response to anti-CD40 + IL-4 becomes completely FK506-resistant within 24 h, whilst that to anti-Ig remains sensitive significantly longer. Secondly, stimulating B cells concurrently via CD40, surface Ig (sIg) and IL-4 receptors invokes an FK506-resistant activation pathway. We previously reported that ligation of either sIg or CD40 receptors, in conjunction with IL-4, induces the transcription factor, nuclear factor of activated T cells (NF-AT) in B cells, via a CsA/FK506-sensitive pathway. However, NF-AT induction elicited by anti-Ig/anti-CD40/IL-4 is still FK506 sensitive, implying that the drug resistance of the response to these three stimuli involves additional components than NF-AT. These results indicate that CD40 activates murine B cells via a Ca(++)-dependent pathway. In agreement with this, anti-CD40 induces a modest increase in intracellular Ca++ levels in these cells, which appears to be largely due to Ca++ influx through the plasma membrane.
免疫抑制药物环孢素A（CsA）和FK506可选择性地消除T细胞和B细胞中Ca(++)调节的激活途径。我们在此表明，抗CD40诱导的小鼠B细胞增殖，无论有无白细胞介素-4（IL-4），都像对抗免疫球蛋白（Ig）的反应一样，可被1-5 ng/ml（导致50%抑制的浓度约为1 nM）的FK506消除。然而，该药物对抗Ig或抗CD40引发的增殖反应的影响有显著差异：首先，对抗CD40 + IL-4的反应在24小时内完全对FK506产生抗性，而对抗Ig的反应在更长时间内仍保持敏感。其次，通过CD40、表面Ig（sIg）和IL-4受体同时刺激B细胞会引发一条对FK506有抗性的激活途径。我们之前报道过，sIg或CD40受体的连接，与IL-4一起，通过一条对CsA/FK506敏感的途径在B细胞中诱导转录因子——活化T细胞核因子（NF-AT）。然而，抗Ig/抗CD40/IL-4诱导的NF-AT仍对FK506敏感，这意味着对这三种刺激的反应产生的药物抗性涉及除NF-AT之外的其他成分。这些结果表明，CD40通过一条Ca(++)依赖性途径激活小鼠B细胞。与此一致的是，抗CD40可使这些细胞内的Ca++水平适度升高，这似乎主要是由于Ca++通过质膜内流所致。
