Th1 versus Th2 cytokine profile determines the modulation of in vitro T cell-independent type 2 responses by IL-4

Abstract

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.

Asthma Status and Waning of Measles Antibody Concentrations after Measles Immunization

“…Vos et al reported early and brief exposure (4 hours) of B cells to IL-4 enhanced a subsequent immunoglobulin secretory response but the continued presence of IL-4 during B cell stimulation suppressed antibody responses in a mouse model. 38 Whether our study findings are related to the results reported by Vos et al needs to be studied in the future.…”

Cytokine-deficient mice as a model for generation of autologous anti-cytokine monoclonal antibodies

“…Representative results from testing of eight anti-IL-4-specific clones and ten anti-IL-13-specific clones are shown. in vitro, early and brief exposure of B cells to IL-4 enhances Ig secretory response to subsequent stimulation with dextranconjugated anti-IgD mAbs in the presence of Th1-dependent cytokines, while continuous exposure results in the inhibition of the response [16]. In accord with these data, the results here suggest a possibility for induction of high-zone T-B-cell tolerance that may explain the absence of increase in Ab response at total doses of immunizing cytokines beyond 100 g. In particular, blocking effect of high doses of cytokines on differentiation and Ag-presenting function of dendritic cells [30] may be responsible for induction of such T-B-cell tolerance.…”

“…IL-4-and IL-13-deficient mice show impaired development of Th2 cells [7,8,15] that produce a panel of cytokines favoring humoral immune response, including IL-4 and IL-13 [16]. Because IL-4 and IL-13 use common ␣-receptor chain and share many biological activities, such as participation in B-cell development and switching of Ig synthesis [17][18][19][20], IL-4KO mice and IL-13KO mice demonstrate several common defects in Ig synthesis.…”

What Does Tympanostomy Tube Placement in Children Teach Us About the Association Between Atopic Conditions and Otitis Media?

“…108 Several mouse and human studies have showed that asthma status, house-dust mite sensitization, and Th2 cytokines impair humoral immune responses to S. pneumoniae, H. influenza , and B. pertussis. 109-112 …”