CD30 signaling negatively regulates CD40-induced immunoglobulin class switching in human B cells. A mechanism for preferential differentiation of antigen selected germinal center B cells

Triggering of B cell Ag receptor (BCR) and CD40 provides the main drive for human B cell germinal center (GC) proliferation and differentiation. BCR signaling is negatively regulated by B cell surface inhibitory molecules, the lack of which can lead to uncontrolled B cell clonal expansion in response to antigenic stimulation. As for CD40, no surface inhibitory molecules have been so far identified. We have used our recently identified monoclonal model of GC B cell differentiation, IgM⁺ IgD⁺ CD30⁺ CL-01 cells, to investigate the role of CD30 in human B cell maturation. CL-01 cells switch to IgG, IgA, and IgE in response to CD40L and IL-4. This switching is effectively hampered by coengagement of CD30 by an agonistic mAb, possibly through interference with the CD40-mediated NF-κB-dependent transcriptional activation of downstream Cγ, Cα, and C∈ genes. The physiological relevance of CD30-mediated inhibition of Ig class switching is emphasized by similar CD30-mediated effects in freshly isolated naive B cells. Effective expression of CD30 by these cells is induced by engagement of CD40 by CD40L, but is inhibited by BCR coengagement. These findings indicate that CD30 negatively modulates CD40-induced Ig class switching, and suggest that CD30 plays a major role in the regulation of human B cell GC differentation.