Involvement of a rapamycin-sensitive pathway in CD40-mediated activation of murine B cells in vitro

Activation of resting B cells requires an initial triggering of the B cell antigen receptor (BCR) and secondary stimuli through various cytokine recep tors and B cell activation molecules including CD40. We found that activati on of B cells through CD40 is selectively inhibited by an immunosuppressant drug, rapamycin. This effect of rapamycin on anti-CD40-mediated activation of B cells was observed using three different in vitro assays. Rapamycin s uppressed the anti-CD40-induced proliferation of splenic B cells, suppresse d differentiation to surface IgM(high)/IgD(low) B cells, and inhibited an a nti-CD40-mediated prevention of apoptosis induced by BCR cross-linkage of W EHI-231 cells. We next examined several known CD40 signal transduction path ways to identify the target of rapamycin in stimulated B cells. Rapamycin d id not inhibit the activation of c-Jun N-terminal kinases (JNKs) induced by anti-CD40 stimulation nor the activation of immediate nuclear transcriptio n factors of NF-KB. Therefore, rapamycin affects a novel element of the CD4 0 signal transduction pathway which influences the proliferation, different iation, and prevention of apoptosis of B cells. (C) 1999 Elsevier Science B .V. All rights reserved.