The 26-kD transmembrane form of tumor necrosis factor alpha on activated CD4+ T cell clones provides a costimulatory signal for human B cell activation.
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 alpha (mTNF-alpha), 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-alpha 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-alpha were still detectable 72 h after activation. The presence of the 26-kD membrane form of TNF-alpha on activated T cell clones was confirmed by immunoprecipitation. Monoclonal antibodies (mAbs) recognizing mTNF-alpha, 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-alpha 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-alpha mAbs strongly reduced their capacity to stimulate B cells to produce Ig in the presence of IL-4, indicating that the anti-TNF-alpha mAbs blocked the effects of mTNF-alpha. Anti-TNF-alpha 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-alpha mAbs indeed interfered with the costimulatory, contact-mediated signal provided by T cells, or their membranes. Collectively these results indicate that mTNF-alpha, 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-alpha.
Aversa
G
G
Human Immunology Department, DNAX Research Institute, Palo Alto, California 94304.
Punnonen
J
J
de Vries
J E
JE
D000911:Antibodies, Monoclonal / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002450:Cell Communication; D002999:Clone Cells; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D007372:Interferons / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008213:Lymphocyte Activation; D011956:Receptors, Cell Surface / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D000911:Antibodies, Monoclonal; D007136:Immunoglobulins; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007372:Interferons