The Journal of Experimental Medicine
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Published 17 November 2003. doi:10.1084/jem.20030357
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© Rockefeller University Press, 0022-1007/2003/11/1609 $5.00
The Journal of Experimental Medicine, Volume 198, Number 10, 1609-1619

A Fail-safe Mechanism for Negative Selection of Isotype-switched B Cell Precursors Is Regulated by the Fas/FasL Pathway

Jane Seagal1, Efrat Edry1, Zohar Keren1, Nira Leider1, Ofra Benny2, Marcelle Machluf2 and Doron Melamed1,3

1 Department of Immunology, Bruce Rappaport Faculty of Medicine
2 Faculty of Food Engineering and Biotechnology, Technion-Israel Institute of Technology, Haifa 31096, Israel
3 Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa 31096, Israel

Address correspondence to Doron Melamed, Department of Immunology, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel. Phone: 972-4-829-5237; Fax: 972-4-829-5245; email: melamedd{at}techunix.technion.ac.il

In B lymphocytes, immunoglobulin (Ig)M receptors drive development and construction of naive repertoire, whereas IgG receptors promote formation of the memory B cell compartment. This isotype switching process requires appropriate B cell activation and T cell help. In the absence of T cell help, activated B cells undergo Fas-mediated apoptosis, a peripheral mechanism contributing to the establishment of self-tolerance. Using Igµ-deficient µMT mouse model, where B cell development is blocked at pro-B stage, here we show an alternative developmental pathway used by isotype-switched B cell precursors. We find that isotype switching occurs normally in B cell precursors and is T independent. Ongoing isotype switching was found in both normal and µMT B cell development as reflected by detection of IgG1 germline and postswitch transcripts as well as activation-induced cytidine deaminase expression, resulting in the generation of IgG-expressing cells. These isotype-switched B cells are negatively selected by Fas pathway, as blocking the Fas/FasL interaction rescues the development of isotype-switched B cells in vivo and in vitro. Similar to memory B cells, isotype-switched B cells have a marginal zone phenotype. We suggest a novel developmental pathway used by isotype-switched B cell precursors that effectively circumvents peripheral tolerance requirements. This developmental pathway, however, is strictly controlled by Fas/FasL interaction to prevent B cell autoimmunity.

Key Words: lymphopoiesis • B cell antigen receptor • immune tolerance • apoptosis • autoimmunity


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