PROPERTIES OF MOUSE CD40 - LIGATION OF CD40 ACTIVATES B-CELLS VIA A CA++-DEPENDENT, FK506-SENSITIVE PATHWAY

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.