title: CD21/CD19 coreceptor signaling promotes B cell survival during primary immune responses.
abstract: The adaptive immune response is tightly regulated to limit responding cells in an Ag-specific manner. On B cells, coreceptors CD21/CD19 modulate the strength of BCR signals, potentially influencing cell fate. The importance of the CD95 pathway was examined in response of B cells to moderate affinity Ag using an adoptive transfer model of lysozyme-specific Ig transgenic (HEL immunoglobulin transgene (MD4) strain) B cells. Although adoptively transferred Cr2+/+ MD4 B cells are activated and persist within splenic follicles of duck egg lysozyme-immunized mice, Cr2-/- MD4 B cells do not. In contrast, Cr2-/- MD4 lpr B cells persist after transfer, suggesting that lack of CD21/CD35 signaling results in CD95-mediated elimination. Cr2 deficiency did not affect CD95 levels, but cellular FLIP (c-FLIP) protein and mRNA levels were reduced 2-fold compared with levels in Cr2+/+ MD4 B cells. In vitro culture with Cr2+/+ MD4 B cells demonstrated that equimolar amounts of rHEL-C3d3 were more effective than hen egg lysozyme alone in up-regulating c-FLIP levels and for protection against CD95-mediated apoptosis. Collectively, this study implies a mechanism for regulating B cell survival in vivo whereby the strength of BCR signaling (including coreceptor) determines c-FLIP levels and protection from CD95-induced death.
authors.affiliation: CBR Institute for Biomedical Research and Department of Pathology, Harvard University, Boston, MA 02115, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Barrington
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhong
authors.forename: Helena
authors.initials: H
authors.lastname: Jonsson
authors.forename: Nichol
authors.initials: N
authors.lastname: Holodick
authors.forename: Anu
authors.initials: A
authors.lastname: Cherukuri
authors.forename: Susan K
authors.initials: SK
authors.lastname: Pierce
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Rothstein
authors.forename: Michael C
authors.initials: MC
authors.lastname: Carroll
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000502:physiology*; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology* / Q000502:physiology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002470:Cell Survival; D015933:Complement C3d / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D009113:Muramidase / Q000276:immunology; D017463:Receptors, Complement 3b / Q000502:physiology; D017464:Receptors, Complement 3d / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology
chemical_list: D018941:Antigens, CD19; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D017463:Receptors, Complement 3b; D017464:Receptors, Complement 3d; D019014:fas Receptor; D015933:Complement C3d; D009113:Muramidase