Effect of cell:cell competition and BAFF expression on peripheral B cell tolerance and B-1 cell survival in transgenic mice expressing a low level of Igkappa-reactive macroself antigen.
In mice carrying a synthetic Igkappa-reactive superantigen ("kappa macroself antigen"), low level expression induced split peripheral B cell tolerance in the sIgkappa+ compartment, with striking reductions in follicular and marginal zone (MZ) B cells and the retention of significant numbers of sIgkappa+ B-1a but not B-1b cells in the peritoneum. Here, we characterize the transgenic line pKkappa with this split tolerance phenotype and assess the effects of B cell competition and the survival cytokine BAFF (B cell activating factor belonging to the TNF family) on peripheral tolerance. In pKkappa mice the surviving peritoneal and splenic kappa+ B cells were largely lost in mice carrying one copy of the human Ckappa exon in place of the mouse version, a maneuver that generates additional antigen non-reactive competitor B cells in this model. Furthermore, overexpression of BAFF suppressed kappa-macroself antigen-induced deletion and promoted production of both IgM,kappa and IgA,kappa antibodies in mice with normal Igkappa alleles but not in mice carrying one copy of the human Ckappa allele. These findings suggest that BAFF overexpression has minimal effects on the survival of autoreactive B cells in a polyclonal immune system and that B cell:B cell competition plays a potent role in suppressing the survival of B-1 and splenic B cells with excessive autoreactivity.
Aït-Azzouzene
Djemel
D
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA. djamait@scripps.edu
Gavin
Amanda L
AL
Skog
Patrick
P
Duong
Bao
B
Nemazee
David
D
D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D053264:B-Cell Activating Factor; D001402:B-Lymphocytes / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology*; D002470:Cell Survival; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007145:Immunoglobulin kappa-Chains / Q000276:immunology*; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000276:immunology
D001324:Autoantigens; D053264:B-Cell Activating Factor; D007145:Immunoglobulin kappa-Chains; D008565:Membrane Proteins; C505719:TNFSF13B protein, human; C505720:Tnfsf13b protein, mouse; D014409:Tumor Necrosis Factor-alpha