International Immunology Advance Access originally published online on August 8, 2008
International Immunology 2008 20(10):1279-1287; doi:10.1093/intimm/dxn087
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Influence of Fas on the regulation of the response of an anti-nuclear antigen B cell clonotype to foreign antigen
1 Department of Microbiology and Immunology, Thomas Jefferson University, Jefferson Alumni Hall 471, 1020 Locust Street, Philadelphia, PA 19107, USA
2 Present address: Department of Pathology, University of Maryland Medical School, Baltimore, MD, USA
Correspondence to: T. Manser; E-mail: manser{at}mail.jci.tju.edu
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.
Keywords: B cell, Fas death receptor, Fas ligand, germinal center, tolerance
Transmitting editor: J. Ravetch
Received 10 March 2008, accepted 1 July 2008.
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