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 regulation 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 enhancer. 4-Hydroxy-3-nitrophenylacetyl (NIP)-BSA induction of a K46 B cell line expressing a chimeric NIP-specific CD40 single chain receptor results in a ligand receptor-dependent response of a 3' enhancer ETS/AP-1 minimal promoter construct. Gel retardation analysis and genomic footprinting experiments reveal that CD40 or IgM induction recruits NFAB (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 signalling, however, induces a Fos family-related partner for JunB, which may account for the transcriptional activity observed by NFAB-II in K46 cells. We propose a model whereby CD40 and IgM receptor-mediated signalling converge in the process of 3' enhancer activation in B lymphocytes. Our data provide a putative molecular explanation as to why CD40L-deficient mice, and possibly patients with hyper-IgM syndrome, are unable to undergo T cell-dependent class switch recombination but respond properly upon lipopolysaccharide-induced switch recombination.
Grant
P A
PA
Center For Biotechnology, Karolinska Institute, Novum, Huddinge, Sweden.
Andersson
T
T
Neurath
M F
MF
Arulampalam
V
V
Bauch
A
A
Müller
R
R
Reth
M
M
Pettersson
S
S
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000096:biosynthesis / Q000276:immunology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005803:Genes, Immunoglobulin; D017930:Genes, Reporter; D005914:Globins / Q000096:biosynthesis; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis* / Q000235:genetics*; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection
D019013:CD40 Antigens; D004268:DNA-Binding Proteins; C512897:ELF1 protein, human; C512896:Elf1 protein, mouse; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D009687:Nuclear Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D005914:Globins