Integrating signals from IFN-gamma and IL-4 by B cells: Positive and negative effects on CD40 ligand-induced proliferation, survival, and division-linked isotype switching to IgG1, IgE, and IgG2a

IL-4 and IFN-gamma each have potent effects on B cell responses as well as strong mutual antagonism. Here me have examined the quantitative effects of these cytokines on CD40 ligand-induced B cell proliferation, cell survival , and division-linked isotype snitching. Both IL-4 (strongly) and IFN-gamma (weakly) enhanced the number of B cells found in culture by reducing the a verage time cells take to enter the first division cycle and by promoting B cell survival. When added in combination, the net effect of IL-4 and IFN-g amma on time to division and survival was a response intermediate between t hat of the two cytokines alone, indicating a partial antagonism of IL-4 by IFN-gamma, By modulating both time to division and cell survival, these sma ll effects of IFN-gamma are amplified and give rise to large reductions in cell number in the presence of IL-4. At higher concentrations, IFN-gamma ha d minor inhibitory effects on IL-4-induced isotype switching to IgG1 and gr eater effects on IgE, A reciprocal relation was observed between the abilit y to inhibit IgE at late cell divisions vs induction of IgG2a, In contrast, IL-4 did not prevent switching to IgG2a induced by IFN-gamma alone. Theref ore, antagonism between IFN-gamma and IL-4 is observed at multiple levels a nd over different concentration ranges, resulting in complex net outcomes. The evolutionary significance of this complexity is discussed.