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.
Klaus
G G
GG
Laboratory of Cellular Immunology, National Institute for Medical Research, Mill Hill, London, GB.
Choi
M S
MS
Holman
M
M
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology*; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens; D023201:CD40 Ligand; D002118:Calcium / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D016559:Tacrolimus / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011947:Receptors, Antigen, B-Cell; D014157:Transcription Factors; D023201:CD40 Ligand; D015847:Interleukin-4; D016572:Cyclosporine; D002118:Calcium; D016559:Tacrolimus