title: VprBP Is Required for Efficient Editing and Selection of Igκ+ B Cells, but Is Dispensable for Igλ+ and Marginal Zone B Cell Maturation and Selection.
abstract: B cell development past the pro-B cell stage in mice requires the Cul4-Roc1-DDB1 E3 ubiquitin ligase substrate recognition subunit VprBP. Enforced Bcl2 expression overcomes defects in distal VH-DJH and secondary Vκ-Jκ rearrangement associated with VprBP insufficiency in B cells and substantially rescues maturation of marginal zone and Igλ(+) B cells, but not Igκ(+) B cells. In this background, expression of a site-directed Igκ L chain transgene increases Igκ(+) B cell frequency, suggesting VprBP does not regulate L chain expression from a productively rearranged Igk allele. In site-directed anti-dsDNA H chain transgenic mice, loss of VprBP function in B cells impairs selection of Igκ editor L chains typically arising through secondary Igk rearrangement, but not selection of Igλ editor L chains. Both H and L chain site-directed transgenic mice show increased B cell anergy when VprBP is inactivated in B cells. Taken together, these data argue that VprBP is required for the efficient receptor editing and selection of Igκ(+) B cells, but is largely dispensable for Igλ(+) B cell development and selection, and that VprBP is necessary to rescue autoreactive B cells from anergy induction.
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University, Omaha, NE 68178.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Palmer
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University, Omaha, NE 68178.
authors.forename: Razia
authors.initials: R
authors.lastname: Aziz-Seible
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University, Omaha, NE 68178.
authors.forename: Michele D
authors.initials: MD
authors.lastname: Kassmeier
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University, Omaha, NE 68178.
authors.forename: Mary
authors.initials: M
authors.lastname: Rothermund
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University, Omaha, NE 68178.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Perry
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University, Omaha, NE 68178 pswanson@creighton.edu.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Swanson
mesh_terms: D000483:Alleles; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D002462:Cell Membrane / Q000378:metabolism; D017635:Clonal Anergy / Q000235:genetics; D060966:Clonal Selection, Antigen-Mediated / Q000235:genetics*; D015870:Gene Expression; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D007145:Immunoglobulin kappa-Chains / Q000235:genetics* / Q000378:metabolism; D007146:Immunoglobulin lambda-Chains / Q000235:genetics* / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D051757:PAX5 Transcription Factor / Q000235:genetics; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D060152:V(D)J Recombination; D000099218:Interferon Regulatory Factor-4
chemical_list: D002352:Carrier Proteins; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D050835:Interferon Regulatory Factors; D051757:PAX5 Transcription Factor; D017346:Protein Serine-Threonine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2; D000099218:Interferon Regulatory Factor-4; C497282:Pax5 protein, mouse; C571226:VprBP protein, mouse