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 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.
Hasbold
J
J
Centenary Institute of Cancer Medicine and Cell Biology, Newtown, Australia.
Hong
J S
JS
Kehry
M R
MR
Hodgkin
P D
PD
D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand; D002455:Cell Division / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D007073:Immunoglobulin E / Q000096:biosynthesis*; D007074:Immunoglobulin G / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000502:physiology*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008024:Ligands; D018655:Lymphocyte Count; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008808:Mice, Inbred CBA; D015398:Signal Transduction / Q000276:immunology*
D000276:Adjuvants, Immunologic; D019013:CD40 Antigens; D007074:Immunoglobulin G; D008024:Ligands; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma