Inhibitory and stimulatory signaling via immunoglobulin receptors: dichotomous responses elicited in clonal B cell populations.

The paradox that cross-linking of IgM antigen receptors on B cells by native or surrogate antigen can inhibit, as well as stimulate, B cell functions has previously been attributed to changes during maturation and activation, programming either a negative or a positive response at defined developmental stages. In contrast to this concept, we show here that some B cells possess the potential for both types of response at the same stage. In three clonal malignant human B cell populations, bivalent soluble monoclonal antibodies to IgM or idiotype, but not IgD completely inhibited spontaneous DNA synthesis, but significantly induced [3H]thymidine uptake when coupled to insoluble compounds. In co-incubation experiments mitogenic stimuli were dominant over inhibitory ones and were still effective after prolonged pretreatment of the B cells with inhibitory reagents. Ionomycin, known to increase intracellular calcium levels, and low doses of phorbol ester, described to activate protein kinase C, also suppressed DNA synthesis. High doses of phorbol ester alone or in combination with ionomycin, however, induced DNA synthesis in two of the lymphomas. We conclude that some B cells may respond to cross-linking of surface IgM in a dose-dependent manner so that all signals increase DNA synthesis once a threshold has been reached. These dose-dependent effects may in part involve signaling via breakdown of membrane inositol phosphates.