title: Mechanism for pre-B cell loss in VH-mutant rabbits.
abstract: Pre-BCR signaling is a critical checkpoint in B cell development in which B-lineage cells expressing functional IgH μ-chain are selectively expanded. B cell development is delayed in mutant ali/ali rabbits because the a-allotype encoding V(H)1 gene, which is normally used in VDJ gene rearrangements in wt rabbits, is deleted, and instead, most B-lineage cells use the a-allotype encoding V(H)4 gene [V(H)4(a)], which results in a severe developmental block at the pre-B cell stage. We found that V(H)4(a)-utilizing pre-B cells exhibit reduced pre-BCR signaling and do not undergo normal expansion in vitro. Transduction of murine 38B9 pre-B cells with chimeric rabbit-VDJ mouse-Cμ encoding retroviruses showed V(H)4(a)-encoded μ-chains do not readily form signal-competent pre-BCR, thereby explaining the reduction in pre-BCR signaling and pre-B cell expansion. Development of V(H)4(a)-utilizing B cells can be rescued in vivo by the expression of an Igκ transgene, indicating that V(H)4(a)-μ chains are not defective for conventional BCR formation and signaling. The ali/ali rabbit model system is unique because V(H)4(a)-μ chains have the capacity to pair with a variety of conventional IgL chains and yet lack the capacity to form a signal-competent pre-BCR. This system could allow for identification of critical structural parameters that govern pre-BCR formation/signaling.
authors.affiliation: Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL 60153, USA.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Robbins
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Knight
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology*; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D018920:Coculture Techniques; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000378:metabolism*; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D054420:Pre-B Cell Receptors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology* / Q000473:pathology*; D011817:Rabbits; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D054420:Pre-B Cell Receptors