The immunoglobulin heavy-chain locus hs3b and hs4 3′ enhancers are dispensable for VDJ assembly and somatic hypermutation

• Published in: Blood Vol. 102; no. 4; pp. 1421 - 1427
• Main Authors: Morvan, Caroline Le, Pinaud, Eric, Decourt, Catherine, Cuvillier, Armelle, Cogné, Michel
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.08.2003; The Americain Society of Hematology; American Society of Hematology
• Subjects: Alleles; Animals; B-Lymphocytes; B-Lymphocytes - immunology; B-Lymphocytes - physiology; Base Sequence; Biological and medical sciences; Cloning, Molecular; Enhancer Elements (Genetics); Enhancer Elements, Genetic - genetics; Enhancer Elements, Genetic - immunology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Rearrangement, B-Lymphocyte, Heavy Chain; Genetics of the immune response; Immunobiology; Immunoglobulin Heavy Chains; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Joining Region; Immunoglobulin Joining Region - genetics; Immunoglobulin Variable Region; Immunoglobulin Variable Region - genetics; Immunoglobulins; Immunoglobulins - biosynthesis; Immunoglobulins - pharmacology; Immunology; Introns; Introns - genetics; Life Sciences; Locus Control Region; Locus Control Region - genetics; Locus Control Region - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Mutation; Mutation - immunology; Peyer's Patches; Peyer's Patches - immunology; Sequence Deletion; Heavy peptide chain; IgA; Immunoglobulins; Lymph node; Germinative center; Variable region; Rodentia; IgG; B-Lymphocyte; J-Peptide chain; Somatic mutation; Vertebrata; Regulation(control); Enhancer sequence; Mammalia; Gene; Mouse; Animal; Humoral immunity
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2002-12-3827

The more distal enhancers of the immunoglobulin heavy-chain 3′ regulatory region, hs3b and hs4, were recently demonstrated as master control elements of germline transcription and class switch recombination to most immunoglobulin constant genes. In addition, they were shown to enhance the accumulation of somatic mutations on linked transgenes. Since somatic hypermutation and class switch recombination are tightly linked processes, their common dependency on the endogenous locus 3′ enhancers could be an attractive hypothesis. VDJ structure and somatic hypermutation were analyzed in B cells from mice carrying either a heterozygous or a homozygous deletion of these enhancers. We find that hs3b and hs4 are dispensable both for VDJ assembly and for the occurrence of mutations at a physiologic frequency in the endogenous locus. In addition, we show that cells functionally expressing the immunoglobulin M (IgM) class B-cell receptor encoded by an hs3b/hs4-deficient locus were fully able to enter germinal centers, undergo affinity maturation, and yield specific antibody responses in homozygous mutant mice, where IgG1 antibodies compensated for the defect in other IgG isotypes. By contrast, analysis of Peyer patches from heterozygous animals showed that peanut agglutinin (PNAhigh) B cells functionally expressing the hs3b/hs4-deficient allele were dramatically outclassed by B cells expressing the wild-type locus and normally switching to IgA. This study thus also highlights the role of germinal centers in the competition between B cells for affinity maturation and suggests that membrane IgA may promote recruitment in an activated B-cell compartment, or proliferation of activated B cells, more efficiently than IgM in Peyer patches.