Crosslinking of surface lg receptors on mature B cells with mitogenic anti-lg antibodies stimulates phosphoinositide breakdown with subsequent activation of protein kinase C (PKC) and elevation of [Ca2+], 1 leading to B-cell activation. This response can be mimicked using second messenger agonists such as phorbol 12, 13-dibutyrate (PDB) plus a Ca2+ lonophore. Furthermore, Interleukln-4 (IL-4) synergises with sub-mitogenic concentrations of anti-lg (or with PDB) to activate adult B cells. In contrast anti-lg does not activate neonatal B cells but rather desensitizes or kills them. The nature of the signals involved in these effects on neonatal B cells is poorly understood. Here we have investigated the proliferative responses of small, resting B cells from 1-, 4-, 8-, and 12-week-old mice stimulated with combinations of anti-lg, PDS, lonomycin and IL.4. We find that B cells from 8 and 12-week-old mice show an adult pattern of reactivity. B cells from 4-week-old mice respond to high doses of anti-lg, anti-lg + IL-4 and also to PDB + lonomycin + IL-4, but not to PDB + lonomycin alone. Neonatal (1-week-old) B cells respond only to the combination of PDB, lonomycin and IL-4. Most strikingly, pre-incubation of neonatal cells with antl-lg completely abrogates this response, whilst IL-4 renders them refractory to such antl-lg mediated inhibition. Overall, these results suggest that ligation of slg receptors has quite distinct consequences at the second messenger level in immature versus mature B cells and that entry into cell cycle in immature B cells is much more dependent on the presence of additional, presumably T-cell derived, signals.