B cell early response gene expression coupled to B cell receptor, CD40 and interleukin‐4 receptor co‐stimulation: evidence for a role of the egr‐2/krox20 transcription factor in B cell proliferation

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Abstract
B lymphocytes are activated following antigen stimulation of the B cell receptor but require co‐stimulation with accessory molecules provided by interleukin (IL)‐4/CD40 ligand for cell cycle progression and proliferation. By analyzing a panel of 11 early response genes induced by cross‐linking of surface immunoglobulin, we show that CD40 signaling alone induces only 2 genes, c‐myc together with an anonymous gene, 3L3, and that these are distinct from the set of genes induced in response to IL‐4. Co‐stimulation with the proliferative combination of anti‐μ, IL‐4 + CD40 signaling led to a fourfold enhancement of egr‐2/krox20 expression over that seen with anti‐μ alone. Egr‐2 expression/activity was selectively inhibited by the immunosuppressive drug cyclosporin A, and antisense oligonucleotide blockade of Egr‐2 activity elicited a dose‐dependent inhibition of B cell proliferation. Taken together, these observations show that the early gene regulatory programs coupled to different surface receptors on B cells are largely distinct from each other, but that certain genes, exemplified by egr‐2, may represent a point of convergence in the integration of different signaling pathways into the B cell proliferative response.