Anti-CD40 monoclonal antibodies or CD4+ T cell clones and IL-4 induce IgG4 and IgE switching in purified human B cells via different signaling pathways.
IL-4 induces IgE and IgG4 synthesis, but in addition to IL-4, a second signal provided by CD4+ T cells is required. Here we demonstrate that the signal provided by CD4+ T cells can be replaced by anti-CD40 mAb. Highly purified surface (sIgM+) human B cells cultured with soluble anti-CD40 mAb in the presence of IL-4 produced IgM, total IgG, IgG4, and relatively high levels of IgE, indicating that production of these isotypes represented H chain switching and was not the result of a selective outgrowth of isotype committed B cells. No IgA was produced in these cultures. However, the T cell signal was different from the signal provided by anti-CD40 mAb, because in contrast to CD4+ T cells, anti-CD40 mAb failed to induce germ-line epsilon transcripts. However, anti-CD40 mAb strongly enhanced germ-line epsilon mRNA expression induced by IL-4. In addition, IFN-gamma, IFN-alpha, and anti-CD23 mAb, which block IL-4-induced IgE production by PBMC, or B cells cocultured with CD4+ T cell clones, failed to inhibit IgG4 and IgE synthesis induced by anti-CD40 mAb. Finally, anti-CD40 mAb and CD4+ T cell clones had strong synergistic effects on IgG4 and IgE synthesis. These results indicate that different B cell activation pathways can result in IgG4 and IgE switching in the presence of IL-4.
Gascan
H
H
DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, CA 94304-1104.
Gauchat
J F
JF
Aversa
G
G
Van Vlasselaer
P
P
de Vries
J E
JE
D000911:Antibodies, Monoclonal / Q000276:immunology; D000917:Antibody Formation / Q000187:drug effects; D015703:Antigens, CD / Q000276:immunology / Q000502:physiology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology / Q000502:physiology*; D016175:B-Lymphocyte Subsets / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D015152:Blotting, Northern; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis* / Q000235:genetics; D007074:Immunoglobulin G / Q000096:biosynthesis*; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis; D066298:In Vitro Techniques; D007370:Interferon Type I / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D011961:Receptors, Fc / Q000276:immunology; D017455:Receptors, IgE; D015398:Signal Transduction; D014158:Transcription, Genetic
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D007370:Interferon Type I; D011961:Receptors, Fc; D017455:Receptors, IgE; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma