A hypomorphic IgH-chain allele affects development of B-cell subsets and favours receptor editing

• Published in: The EMBO journal 2011-07, Vol.30 (13), p.2705-2718
• Main Authors: Brenner, Sven, Drewel, Diana, Steinbart, Thomas, Weisel, Florian, Härtel, Eric, Pötzsch, Sonja, Welzel, Heike, Brandl, Andreas, Yu, Philipp, Mudde, Geert C, Schweizer, Astrid, Nitschke, Lars, Winkler, Thomas H
• Format: Article
• Language: English
• Subjects: Alleles; Animals; Antibody Formation - genetics; Antibody Formation - physiology; B-Cell Activation Factor Receptor - metabolism; B-cell development; B-cell receptor; B-Lymphocyte Subsets - metabolism; B-Lymphocyte Subsets - physiology; BAFF; Bone marrow; Bone Marrow Cells - immunology; Bone Marrow Cells - metabolism; Bone Marrow Cells - physiology; Cell Differentiation - genetics; Cell Differentiation - immunology; Cells, Cultured; Cellular biology; EMBO19; Gene expression; Genes, Immunoglobulin Heavy Chain - genetics; Genes, Immunoglobulin Heavy Chain - physiology; Immunoglobulin mu-Chains - genetics; Immunoglobulin mu-Chains - metabolism; Immunoglobulins; Immunology; Lectins - genetics; Lectins - immunology; Lectins - metabolism; Lymphocytes; Mice; Mice, Transgenic; Molecular biology; Organs; Precursor Cells, B-Lymphoid - immunology; Precursor Cells, B-Lymphoid - metabolism; Precursor Cells, B-Lymphoid - physiology; receptor editing; Receptors, Antigen, B-Cell - genetics; Receptors, Antigen, B-Cell - immunology; Receptors, Antigen, B-Cell - metabolism; Subpopulations
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2011.168

The quality and quantity of BCR signals impact on cell fate decisions of B lymphocytes. Here, we describe novel gene‐targeted mice, which in the context of normal VDJ recombination show hypomorphic expression of immunoglobulin μ heavy chain (μHC) mRNA levels and hence lower pre‐BCR and BCR levels. Hypomorphic expression of μHC leads to augmented selection processes at all stages of B‐cell development, noticeably at the expansion of pre‐B cells, the positive selection of immature B lymphocytes in the bone marrow and the selection of the follicular (FO), marginal zone (MZ) and B1 B‐lymphocyte compartment in peripheral lymphoid organs. Immature as well as mature FO and MZ B lymphocytes in the peripheral lymphoid organs express lower levels of the receptor for B‐cell activating factor (BAFF). In addition, hypomorphic expression of the BCR favours receptor editing. Together, our results highlight the critical importance of pre‐BCR and BCR receptor levels for the normal development of B‐lymphocyte subpopulations in the context of intact VDJ recombination and a diverse antibody repertoire. A novel mouse model supports the hypothesis that BCR signalling strength is important for the development of B‐lymphocyte subpopulations.