Influence of Fas on the regulation of the response of an anti-nuclear antigen B cell clonotype to foreign antigen.
A peripheral B cell tolerance checkpoint appears to be operative during the germinal center (GC) reaction. We previously showed that a transgenic BCR clonotype that is 'dual reactive' for the hapten arsonate (Ars) and nuclear auto-antigens is stimulated to enter the GC response via Ars immunization. However, the participation of this clonotype in this response wanes with time and it gives rise to few memory B cells capable of mounting a secondary anti-Ars IgG response. Enforced expression of Bcl-2 partially rescues the GC and memory B cell responses of this clonotype, suggesting that apoptotic pathways are involved in the action of the GC tolerance checkpoint. Since GC B cells substantially up-regulate levels of expression of the Fas apoptotic death receptor, we determined whether an intrinsic Fas deficient could rescue the participation of this clonotype in the GC response. It could not, strongly indicating that Fas expression by autoreactive GC B cells is not necessary for their elimination. In addition, experiments in which Fas-sufficient dual reactive clonotype B cells were transferred to Fas-deficient hosts revealed an absence of participation of these B cells in the GC and IgG anti-Ars responses. We present data consistent with the idea that T cells in Fas-deficient hosts are primed to express elevated levels of FasL and eliminate antigen-activated B cells that up-regulate Fas.
Alabyev
Boris
B
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Vuyyuru
Raja
R
Manser
Tim
T
D019264:Adoptive Transfer; D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology; D034961:Antigens, Nuclear / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D006241:Haptens / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics* / Q000276:immunology; D007117:Immunization, Secondary; D007130:Immunoglobulin Idiotypes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007156:Immunologic Memory / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D013997:Time Factors; D019014:fas Receptor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D018033:Antibodies, Bispecific; D034961:Antigens, Nuclear; C491899:Fas protein, mouse; D006241:Haptens; D007130:Immunoglobulin Idiotypes; D019014:fas Receptor