title: Does CD40 ligation induce B cell negative selection?
abstract: Binding of CD154 to its receptor, CD40, provides costimulation for mature B cell activation and differentiation in response to Ag receptor signals. In mice, early B cell precursors express CD40, but its function at this stage is unknown. We examined the effects of CD40 ligation during B cell ontogeny in transgenic mice constitutively expressing CD154 on B cells (kappaEP-CD154). Precursors beyond pro-B cells were absent in adult bone marrow but were increased in the fetal liver. Newborn kappaEP-CD154 mice had largely increased numbers of peripheral B cells, which were CD154+, and that 36 h after birth expressed high surface levels of CD23 and MHC class II, resembling activated mature B cells. Nevertheless, kappaEP-CD154 mice were hypogammaglobulinemic, indicating that the expanded population of apparently activated B cells was nonfunctional. Further analysis revealed that soon after birth, kappaEP-CD154 mice-derived B cells became CD5+/Fas+, after which progressively decreased in the periphery in a CD154-CD40-dependent manner. These results indicate that CD40 ligation during B cell ontogeny induces negative selection characterized by either hyporesponsiveness or an arrest in maturation depending on the time of analysis and the anatomic site studied.
authors.affiliation: Research Unit on Autoimmune Diseases, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, 03020 México City, Distrito Federal, México.
authors.forename: Jesús
authors.initials: J
authors.lastname: Martínez-Barnetche
authors.forename: Vicente
authors.initials: V
authors.lastname: Madrid-Marina
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: José
authors.initials: J
authors.lastname: Moreno
mesh_terms: D000375:Aging / Q000235:genetics / Q000276:immunology; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D019013:CD40 Antigens / Q000096:biosynthesis / Q000378:metabolism*; D023201:CD40 Ligand / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018956:CD5 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D017635:Clonal Anergy; D005333:Fetus; D016130:Immunophenotyping; D008024:Ligands; D008099:Liver / Q000196:embryology / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013234:Stem Cells / Q000276:immunology / Q000473:pathology; D019014:fas Receptor / Q000096:biosynthesis
chemical_list: D019013:CD40 Antigens; D018956:CD5 Antigens; D008024:Ligands; D019014:fas Receptor; D023201:CD40 Ligand