Critical role of B cell lymphoma 10 in BAFF-regulated NF-κB activation and survival of anergic B cells

Mei Yu, Yuhong Chen, Yinghong He, Andrew Podd, Guoping Fu, Jacqueline A. Wright, Eden Kleiman, Wasif N. Khan, Renren Wen, Demin Wang

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Anergy is a key physiological mechanism for restraining self-reactive B cells. A marked portion of peripheral B cells are anergic B cells that largely depend on BAFF for survival. BAFF activates the canonical and noncanonical NF-κB pathways, both of which are required for B cell survival. In this study we report that deficiency of the adaptor protein B cell lymphoma 10 (Bcl10) impaired the ability of BAFF to support B cell survival in vitro, and it specifically increased apoptosis in anergic B cells in vivo, dramatically reducing anergic B cells in mice. Bcl10-dependent survival of self-reactive anergic B cells was confirmed in the Ig hen egg lysozyme/soluble hen egg lysozyme double-transgenic mouse model of B cell anergy. Furthermore, we found that BAFF stimulation induced Bcl10 association with IκB kinase β, a key component of the canonical NF-κB pathway. Consistently, Bcl10-deficient B cells were impaired in BAFF-induced IκBα phosphorylation and formation of nuclear p50/c-Rel complexes. Bcl10-deficient B cells also displayed reduced expression of NF-κB2/p100, severely reducing BAFF-induced nuclear accumulation of noncanonical p52/RelB complexes. Consequently, Bcl10-deficient B cells failed to express Bcl-xL, a BAFF-induced NF-κB target gene. Taken together, these data demonstrate that Bcl10 controls BAFF-induced canonical NF-κB activation directly and non-canonical NF-κB activation indirectly. The BAFF-R/Bcl10/NF-κB signaling axis plays a critical role in peripheral B cell tolerance by regulating the survival of self-reactive anergic B cells.

Original languageEnglish (US)
Pages (from-to)5185-5193
Number of pages9
JournalJournal of Immunology
Volume189
Issue number11
DOIs
StatePublished - Dec 1 2012

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Yu, M., Chen, Y., He, Y., Podd, A., Fu, G., Wright, J. A., Kleiman, E., Khan, W. N., Wen, R., & Wang, D. (2012). Critical role of B cell lymphoma 10 in BAFF-regulated NF-κB activation and survival of anergic B cells. Journal of Immunology, 189(11), 5185-5193. https://doi.org/10.4049/jimmunol.1102952