Immunoregulatory role of CD40 in human B cell differentiation

CD40 is a member of a family of surface molecules with homology to the nerve growth factor receptor and is expressed on B cells. The role of CD40 in regulating human B cell differentiation and the production of specific Ig isotypes was examined. In the absence of other stimuli, anti-CD40 and IL-4 induced the secretion of IgM, IgG, and IgE by purified human peripheral blood B cells. However, addition of formalinized Staphylococcus aureus (SA) enhanced the response. In the presence of SA, anti-CD40 and IL-4 induced the secretion of IgM, IgG1, IgG2, IgG3, and IgG4 in addition to IgE. No consistent effect on IgA secretion was demonstrated. The combination of SA, anti-CD40, and IL-4 induced one tenth of the total Ig production that was stimulated by SA and IL-2, with a different distribution of Ig H chain isotypes. B cells stimulated with SA, anti-CD40, and IL-4 secreted a greater percentage of IgG4 and IgE and a decreased percentage of IgG1 and IgA, compared with that secreted in response to SA and IL-2. Anti-CD40 did not induce Ig production in combination with IL-2 and did not alter the Ig secreted in response to SA and IL-2. Stimulation with SA, anti-CD40, and IL-4 caused Ig H chain isotype switch, inasmuch as IgG and IgE secretion could be induced from preimmune cord blood B cells and IgD+ naive adult B cells and IgE secretion could be induced from IgE- adult B cells. Ig secretion by purified B cells stimulated with SA, IL-4, and anti-CD40, but not with SA and IL-2, was significantly enhanced by anti-CD18 or anti-ICAM-1 mAb, suggesting that homotypic aggregation induced by anti-CD40 might limit Ig production. Finally, anti-CD40 was found to inhibit Ig production by B cells cultured with anti-CD3-activated T cells. These results suggest that engagement of the CD40 molecule on B cells provides signals that permit IL-4 to induce Ig isotype switching. This response is limited by LFA-1-mediated homotypic interactions of B cells. Engagement of CD40 by the ligand expressed by activated T cells appears to be important for the activation of B cells during T cell-B cell collaboration and the production of all isotypes of Ig.