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 cross-linking, using dextran-conjugated anti-IgD mAb (alpha delta-dex), in the presence of cytokines, is an in vitro model for T cell-independent type 2 (TI-2) Ig secretory responses. Earlier studies have shown that IL-4 enhances IgM secretion upon stimulation with alpha delta-dex plus IL-5 and induces IgG1 isotype-switching, without altering the proliferative response to alpha delta-dex. Here we show that IL-4 can have both stimulatory 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 additions, T(h)1 versus T(h)2, determine whether stimulation or inhibition is observed. Preincubation of sort-purified B cells with IL-4 caused a 6- to 8-fold 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 cytokine combinations tested, except for those which included IL-5. Of 11 cytokines tested, only IL-4 showed this dual effect of enhancement and suppression. The stimulatory effect of IL-4 required a minimum of 4 h of preincubation and could be inhibited by the addition of IFN-gamma. Thus stimulation of non-MHC class II-dependent T or non-T cells by multivalent antigens to secrete 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 TI-2 response in the presence of T(h)1-dependent cytokines, while continuous exposure will result in inhibition of the response.
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Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799, USA.
Snapper
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CM
Mond
J J
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D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000032:analysis*; D003911:Dextrans / Q000494:pharmacology; D015151:Immunoblotting; D007136:Immunoglobulins / Q000032:analysis*; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D013997:Time Factors
D000911:Antibodies, Monoclonal; D016207:Cytokines; D003911:Dextrans; D007136:Immunoglobulins; D015847:Interleukin-4; D007371:Interferon-gamma