Deficiency in Msh2 affects the efficiency and local sequence specificity of immunoglobulin class-switch recombination: parallels with somatic hypermutation.
During maturation of the immune response, IgM+ B cells switch to expression of one of the downstream isotypes (IgG, A or E). This class switching occurs by region-specific recombination within the IgH locus through an unknown mechanism. A lack of switch recombination in mice deficient in components of the DNA-dependent protein kinase (DNA-PK)-Ku complex has pointed to a role for non-homologous end joining. Here we characterize a switching defect in mice lacking a protein involved in DNA mismatch recognition. Mice deficient in Msh2 give diminished IgG (but not IgM) responses following challenge with both T cell-dependent and T cell-independent antigens. This appears to reflect a B cell-intrinsic defect since B cells from Msh2-deficient mice also exhibit impaired switching (but not blasting or proliferation) on in vitro culture with lipopolysaccharide. Furthermore, those switches that do occur in Msh2-deficient B cells reveal a shift in the distribution of recombination sites used: the breakpoints are more likely to occur in consensus motifs. These results, which intriguingly parallel the effects of Msh2 deficiency on hypermutation, suggest a role for Msh2 in the mechanics of class-switch recombination.
Ehrenstein
M R
MR
Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.
Neuberger
M S
MS
D000818:Animals; D000955:Antigens, T-Independent / Q000276:immunology / Q000494:pharmacology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020137:Base Pair Mismatch / Q000235:genetics; D001483:Base Sequence; D002478:Cells, Cultured; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins; D005362:Ficoll / Q000031:analogs & derivatives / Q000494:pharmacology; D007070:Immunoglobulin A / Q000235:genetics; D017578:Immunoglobulin Class Switching / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000235:genetics; D007075:Immunoglobulin M / Q000097:blood / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D051718:MutS Homolog 2 Protein; D016296:Mutagenesis / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D010581:Peyer's Patches / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic / Q000187:drug effects / Q000235:genetics
D000955:Antigens, T-Independent; D004268:DNA-Binding Proteins; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D005362:Ficoll; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein