IL-4 and anti-CD40 protect against Fasmediated B cell apoptosis and induce B cell growth and differentiation

Most Th2 clones, when activated, produce IL-4 and express CD40 ligand (CD40L) on their cell surface. Therefore, they can induce growth and differentiation of B cells by cognatehelp. In contrast, activated Th1 clones, which produce IFN-γ and express both CD40L and Fas ligand (FasL) on their cell surface, often induce B cell apoptotic cell death. Tounderstand the mechanism by which Th2 cells can induce B cell growth and differentiation in the presence of FasL-positive cells, we stimulated B cells with IL-4, anti-IgM and/or anti-CD40 in the presence of anti-Fas. We report here that addition of anti-Fas strongly inhibited anti-CD40-induced B cell proliferation without affecting anti-IgM-induced B cell proliferation. Furthermore we showed that stimulation of B cells with anti-CD40 induced the expressionof Fas molecules on the B cells (˜30%) and rendered them highly sensitive to anti-Fas-mediated apoptotic cell death. Indeed, over 23% of anti-CD40-stimulated B cells showed hypodiploid DNA after being incubated with anti-Fas, while >2% of anti-CD40-stimulated B cells showed hypodiploid DNA after being incubated with medium alone. We also showed that IL-4 enhanced expression of Fas on anti-CD40-induced B cells (˜50%), although co-stimulation with anti-CD40 and IL-4 protected B cells from anti-Fas-mediated apoptotic cell death and induced their growth and differentiation. Our present result might suggest that Th2 cells could dominate over FasL-positive Th1 cells by production of CD40L and IL-4, which in combination induce antibody production and inhibit the Th1 cell-mediated immune response.