title: 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.
abstract: Given the range of mIg-binding affinities expressed by Ag-specific B cells, the ligand:receptor affinity threshold for achieving full B cell activation via the mIgM-mediated signaling pathway is quite high. Several recombinant, or semi-purified, cytokines were found to reduce the very high mIgM:ligand affinity threshold for induction of human B cell S phase entry by bivalent, affinity-diverse anti-IgM mAbs without notably affecting the lower affinity threshold for G1-related RNA synthesis. 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 affinity threshold for S phase entry is an indirect one, i.e., rescue of B cells whose mIg engagements with Ag are of sufficient affinity for achieving G1 entry, but of insufficient affinity for initiating the late-phase mIgM-mediated signals needed for the G1-->S phase transition. IL-4 had additional effects in early G1. In contrast to the above cytokines, IFN-gamma, did not function as an independent cell cycle progression factor, but rather required the concomitant presence of mIgM-cross-linking ligand for enhancement. A greater potential of multivalent 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 indicate that progression of mIgM receptor-activated B cells past a G1-->S phase restriction point is dependent upon continued signal transduction via either the mIgM receptor and/or a cytokine receptor signaling pathway. When mIgM-engaging ligands are ineffective at initiating late-phase signals, due to limited size and binding site valency and/or affinity, ancillary signal transduction through cytokine receptors becomes most relevant.
authors.affiliation: Department of Rheumatology and Molecular Medicine, Hospital for Joint Diseases, New York, NY 10003, USA.
authors.forename: P K
authors.initials: PK
authors.lastname: Mongini
authors.forename: P F
authors.initials: PF
authors.lastname: Highet
authors.forename: J K
authors.initials: JK
authors.lastname: Inman
mesh_terms: D000915:Antibody Affinity; D001402:B-Lymphocytes / Q000276:immunology*; D002453:Cell Cycle; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000276:immunology / Q000494:pharmacology*; D016193:G1 Phase; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology / Q000494:pharmacology*; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D014066:Palatine Tonsil / Q000276:immunology; D016196:S Phase
chemical_list: D016207:Cytokines; D007075:Immunoglobulin M; D008024:Ligands