The 26-kD transmembrane form of tumor necrosis factor a on activated CD4+ T cell clones provides a costimulatory signal for human B cell activation

Abstract

Interleukin 4 (IL-4) induces immunoglobulin (Ig)E and IgG4 synthesis in human B cells. In addition to IL-4, costimulatory signals provided by activated CD4+ T cells are required for productive IgG4 and IgE synthesis. Here we report that the 26-kD transmembrane form of tumor necrosis factor a (mTNF-α), which is rapidly expressed on CD4+ T cell clones after activation, contributes to the costimulatory signals resulting in IL-4-dependent Ig synthesis by B cells, including IgG4 and IgE production. mTNF-α expression was induced on T cell clones within 2 h after activation with concanavalin A. Peak expression was observed at 24 h, followed by a gradual decrease, but appreciable levels of mTNF-α were still detectable 72 h after activation. The presence of the 26-kD membrane form of TNF-α on activated T cell clones was confirmed by immunoprecipitation. Monoclonal antibodies (mAbs) recognizing mTNF-α, or the p55 TNF receptor, inhibited IgM, IgG, IgG4, and IgE synthesis induced by IL-4 and activated CD4+ T cell clones in cultures of highly purified surface IgD+ B cells. The anti-TNF-α mAbs also blocked Ig production in cultures in which the activated CD4+ T cell clones were replaced by their plasma membranes. Furthermore, pretreatment of the plasma membranes with anti-TNF-α mAbs strongly reduced their capacity to stimulate B cells to produce Ig in the presence of IL-4, indicating that the anti-TNF-α mAbs blocked the effects of mTNF-α. Anti-TNF-α mAbs did not affect IgM, IgG, IgG4, or IgE synthesis induced by anti-CD40 mAbs and IL-4 in the absence of CD4+ T cells, supporting the notion that the anti-TNF-α mAbs indeed interfered with the costimulatory, contact-mediated signal provided by T cells, or their membranes. Collectively these results indicate that mTNF-α, which is rapidly induced after activation of CD4+ T cells, participates in productive T-B cell interactions resulting in IL-4-induced Ig production. This is a novel property of the T cell membrane form of TNF-α.