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

Jane Seagal, Efrat Edry, Zohar Keren, Nira Leider, Ofra Benny, Marcelle Machluf, Doron Melamed*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)1609-1619
Number of pages11
JournalJournal of Experimental Medicine
Volume198
Issue number10
DOIs
StatePublished - 17 Nov 2003
Externally publishedYes

Bibliographical note

Funding Information:
1Department of Physics, Faculty of Mathematics and Natural Sciences, Syiah Kuala University, Darussalam, Banda Aceh 23111, NAD, Indonesia 2Department of Industrial Engineering, University of Pelita Harapan, Lippo Village, Tangerang 15811, Indonesia 3Research Center for Physics, Indonesia Institute of Sciences, Kawasan PUSPIPTEK, Serpong, Tangerang Selatan 15314, Banten, Indonesia 4Department of Electrical Engineering, University of Pelita Harapan, Lippo Village, Tangerang 15811, Indonesia 5Department of Physics, Faculty of Mathematics and Natural Sciences, Udayana University, Kampus Bukit Jimbaran, Denpasar 80361, Bali, Indonesia 6Research Center of Maju Makmur Mandiri Foundation, Kembangan, Jakarta Barat 11630, Indonesia 7Department of Computer Engineering, Bina Nusantara University, Jakarta 14810, Indonesia 8Department of Electrical Engineering, Krida Wacana Christian University, Jakarta 11470, Indonesia 9Physics of Magnetism and Photonics Group, Faculty of Mathematics and Natural Sciences, Bandung Institute of Technology, Bandung 40132, Indonesia 10Fukui Science Education Academy, Fukui 910-0804, Japan

Funding Information:
This work was partially supported through a Basic Research Grant in Physics, The Academy of Sciences for the Developing World, Third World Academy of Sciences (TWAS), under contract No. 060150 RG=PHYS=AS= UNESCO FR:3240144882.

Keywords

  • Apoptosis
  • Autoimmunity
  • B cell antigen receptor
  • Immune tolerance
  • Lymphopoiesis

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