Inhibition of LFA-1-dependent human B-cell aggregation induced by CD40 antibodies and interleukin-4 leads to decreased IgE synthesis.
Antibodies to CD40 have been shown to induce homotypic aggregation of human resting B cells and B-cell lines via an LFA-1-dependent mechanism. We show here that interleukin-4 (IL-4) is a strong potentiator of this process and stimulation of tonsillar B cells for 4 days with IL-4 and CD40 antibodies resulted in the formation of large, dense aggregates. Also in this case, aggregation appeared to be chiefly dependent on the activation of LFA-1, although the small clusters of cells remaining after blocking with LFA-1 antibodies suggest the involvement of another adhesion system(s). When testing the relationship between aggregation and IgE synthesis, a known consequences of IL-4/CD40 stimulation, IgE levels were found to be significantly decreased in the presence of LFA-1 antibodies. In contrast to these observations, proliferation occurring in response to the IL-4/CD40 stimulation was not inhibitable by LFA-1 antibodies. Rather, in most cases, this was slightly enhanced, suggesting that aggregation may have a limiting effect on cell growth. Isolated aggregates, each of which could comprise more than 10(5) cells, were also examined by electron microscopy. This revealed a tissue-like structure of the aggregates with large contact areas and with minimal intercellular space between the adjacent cells. As the apparent inhibitory effect of aggregation on proliferation may reflect a negative autocrine signalling, which is enhanced by the close cell contact, we also tested the effect of neutralizing antibodies to IL-6, one of the factors known to be produced in the system. Such treatment did not affect aggregation but in most experiments enhanced proliferation. The results suggest that a possible effect of aggregation may be to enhance differentiation of cells and that this may also be associated with the difficulties in growing B cells in vitro.
Björck
P
P
Department of Immunology, Arrhenius Laboratories F5, Stockholm University, Sweden.
Paulie
S
S
D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000648:ultrastructure; D019013:CD40 Antigens; D002449:Cell Aggregation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D014066:Palatine Tonsil / Q000276:immunology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D016169:Lymphocyte Function-Associated Antigen-1; D015847:Interleukin-4; D007073:Immunoglobulin E