Bcl-2 rescues the germinal center response but does not alter the V gene somatic hypermutation spectrum in MSH2-deficient mice.
Ab V genes in mice deficient for the postreplication mismatch repair factor MutS homolog (MSH2) have been reported to display an abnormal bias for hypermutations at G and C nucleotides and hotspots. We previously showed that the germinal center (GC) response is severely attenuated in MSH2-deficient mice. This suggested that premature death of GC B cells might preclude multiple rounds of hypermutation necessary to generate a normal spectrum of base changes. To test this hypothesis, we created MSH2-deficient mice in which Bcl-2 expression was driven in B cells from a transgene. In such mice, the elevated levels of intra-GC apoptosis and untimely GC dissolution characteristic of MSH2-deficient mice are suppressed. However, the spectrum of hypermutation is unchanged. These data indicate that the effects of MSH2 deficiency on GC B cell viability and the hypermutation process are distinct.
Alabyev
Boris
B
Kimmel Cancer Center and Department of Microbiology and Immunology, Jefferson Medical College, Thomas Jefferson University Philadelphia, PA 19107, USA.
Manser
Tim
T
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002999:Clone Cells; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation / Q000276:immunology; D005803:Genes, Immunoglobulin / Q000235:genetics*; D019254:Genes, bcl-2 / Q000276:immunology / Q000502:physiology*; D018858:Germinal Center / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051718:MutS Homolog 2 Protein; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019076:Transgenes / Q000276:immunology
D004268:DNA-Binding Proteins; D007135:Immunoglobulin Variable Region; D011518:Proto-Oncogene Proteins; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein