Integrating signals from IFN-γ 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 we have examined the quantitative effects of these cytokines on CD40 ligand-induced B cell proliferation, cell survival, and division-linked isotype switching. Both IL-4 (strongly) and IFN-gamma (weakly) enhanced the number of B cells found in culture by reducing the average 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-gamma on time to division and survival was a response intermediate between that 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 small 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 had minor inhibitory effects on IL-4-induced isotype switching to IgG1 and greater effects on IgE. A reciprocal relation was observed between the ability 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. Therefore, antagonism between IFN-gamma and IL-4 is observed at multiple levels and over different concentration ranges, resulting in complex net outcomes. The evolutionary significance of this complexity is discussed.