Isotype Switching by Human B Cells Is Division-Associated and Regulated by Cytokines1

Isotype switching by murine B cells follows a pattern whereby the proportion of cells undergoing switching increases with division number and is regulated by cytokines. Here we explored whether human B cells behaved in a similar manner. The effect of IL-4, IL-10, and IL-13, alone or in combination, on Ig isotype switching by highly purified naive human CD40 ligand (CD40L)-activated B cells was measured against division number over various harvest times. Switching to IgG was induced by IL-4 and, to a lesser extent, IL-13 and IL-10. The combination of IL-10 with IL-4, but not IL-13, induced a higher percentage of cells to undergo switching. Isotype switching to IgG by human CD40L-activated naive B cells was found to be linked to the division history of the cells: IgG+ cells appeared in cultures of B cells stimulated with CD40L and IL-4 after approximately the third cell division, with the majority expressing IgG1, thus revealing a predictable pattern of IgG isotype switching. These results reveal a useful quantitative framework for monitoring the effects of cytokines on proliferation and isotype switching that should prove valuable for screening Ig immunodeficiencies and polymorphisms in the population for a better understanding of the regulation of human humoral immune responses.