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/

B lymphocytes are activated following antigen stimulation of the B cel l receptor but require co-stimulation with accessory molecules provide d by interleukin (IL)-4/CD40 ligand for cell cycle progression and pro liferation. 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 respons e to IL-4. Co-stimulation with the proliferative combination of anti-m u, IL-4 + CD40 signaling led to a fourfold enhancement of egr-2/krox20 expression over that seen with anti-mu alone. Egr-2 expression/activi ty 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, t hese observations show that the early gene regulatory programs coupled to different surface receptors on B cells are largely distinct from e ach other, but that certain genes, exemplified by egr-2, may represent a point of convergence in the integration of different signaling path ways into the B cell proliferative response.