A T-CELL CONTROLLED MOLECULAR PATHWAY REGULATING THE IGH LOCUS - CD40-MEDIATED ACTIVATION OF THE IGH 3'-ENHANCER

Immunoglobulin heavy chain (IgH) class switch recombination and regula tion of IgH expression levels are processes suggested to be controlled by the IgH 3' enhancer, Here we demonstrate that CD40 or IgM receptor stimulation of primary B cells results in transactivation of this enh ancer, 4-Hydroxy-3-nitrophenylacetyl (NIP)-BSA induction of a K46 B ce ll line expressing a chimeric NIP-specific CD40 single chain receptor results in a ligand receptor-dependent response of a 3' enhancer ETS/A P-1 minimal promoter construct, Gel retardation analysis and genomic f ootprinting experiments reveal that CD40 or IgM induction recruits NFA B (nuclear factors of activated B cells) to the ETS/AP-1 motif, While IgM signalling recruits c-Fos, JunB and Elf-1 (NFAB-I), only JunB and Elf-1 were observed following CD40 signalling (NFAB-II), CD40 signalli ng, however, induces a Fos family-related partner for JunB, which may account for the transcriptional activity observed by NFAB-II in K46 ce lls, We propose a model whereby CD40 and IgM receptor-mediated signall ing converge in the process of 3' enhancer activation in B lymphocytes . Our data provide a putative molecular explanation as to why CD40L-de ficient mice, and possibly patients with hyper-IgM syndrome, are unabl e to undergo T cell-dependent class switch recombination but respond p roperly upon lipopolysaccharide-induced switch recombination.