T(h)1 versus T(h)2 cytokine profile determines the modulation of in vitro T cell-independent type 2 responses by IL-4

We have previously demonstrated that stimulation of B cells by multivalent membrane Ig crosslinking, using dextran-conjugated anti-IgD mAb (alpha delt a-dex), in the presence of cytokines, is an in vitro model for T cell-indep endent type 2 (Tl-2) Ig secretory responses. Earlier studies have shown tha t IL-4 enhances IgM secretion upon stimulation with alpha delta-dex plus IL -5 and induces IgG1 isotype-switching, without altering the proliferative r esponse to alpha delta-dex, Here we show that IL-4 can have both stimulator y and inhibitory effects on alpha delta-dex-induced Ig secretion. Both the kinetics and time of exposure to IL-4, and the nature of the cytokine addit ions, T(h)1 versus T(h)2, determine whether stimulation or inhibition is ob served. Preincubation of sort-purified B cells with IL-4 caused a 6- to 8-f old increase in Ig secretory responses to subsequent stimulation with alpha delta-dex plus IL-1, IL-2 or a combination of both. However, the continued presence of IL-4 during B cell stimulation suppressed responses to all cyt okine combinations tested, except for those which included IL-5, Of 11 cyto kines tested, only IL-4 showed this dual effect of enhancement and suppress ion. The stimulatory effect of IL-4 required a minimum of 4 h of preincubat ion and could be inhibited by the addition of IFN-gamma. Thus Stimulation o f non-MHC class Ii-dependent T or non-T cells by multivalent antigens to se crete IL-4 may regulate the response to these antigens, such that early and brief exposure of B cells to IL-4 will enhance a subsequent Tl-2 response in the presence of T(h)1-dependent cytokines, while continuous exposure wil l result in inhibition of the response.