HUMAN B-CELL ACTIVATION - EFFECT OF T-CELL CYTOKINES ON THE PHYSICOCHEMICAL BINDING REQUIREMENTS FOR ACHIEVING CELL-CYCLE PROGRESSION VIA THE MEMBRANE IGM SIGNALING PATHWAY

Given the range of mIg-binding affinities expressed by Ag-specific B c ells, the ligand:receptor affinity threshold for achieving full B cell activation via the mIgM-mediated signaling pathway is quite high. Sev eral recombinant, or semi-purified, cytokines were found to reduce the very high mIgM:ligand affinity threshold for induction of human B cel l S phase entry by bivalent, affinity-diverse anti-IgM mAbs without no tably affecting the lower affinity threshold for G(1)-related RNA synt hesis. Two-stage culture experiments suggested that one major means by which IL-4 , IL-2, and low m.w. B cell growth factor lower the affini ty threshold for S phase entry is an indirect one, i.e., rescue of B c ells whose mIg engagements with Ag are of sufficient affinity for achi eving G(1) entry, but of insufficient affinity for initiating the late -phase mIgM-mediated signals needed for the G(1)-->S phase transition, IL-4 had additional effects in early G(1). In contrast to the above c ytokines, IFN-gamma, did not function as an independent cell cycle pro gression factor, but rather required the concomitant presence of mIgM- cross-linking ligand for enhancement. A greater potential of multivale nt anti-IgM-dextran conjugates to trigger S phase entry in the absence of cytokines was found to reflect a greater potential for initiating mIgM signals during the late phase in B cell activation, The results i ndicate that progression of mIgM receptor-activated B cells past a G(1 )-->S phase restriction point is dependent upon continued signal trans duction via either the mIgM receptor and/or a cytokine receptor signal ing pathway. When mIgM-engaging ligands are ineffective at initiating late-phase signals, due to limited size and binding site valency and/o r affinity, ancillary signal transduction through cytokine receptors b ecomes most relevant.