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Critical role of B cell lymphoma 10 in BAFF-regulated NF-κB activation and survival of anergic B cells. J Immunol 2012 Dec 01;189(11):5185-93

Date

10/23/2012

Pubmed ID

23087406

Pubmed Central ID

PMC3786778

DOI

10.4049/jimmunol.1102952

Scopus ID

2-s2.0-84869825522   10 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-x(L), a BAFF-induced NF-κB target gene. Taken together, these data demonstrate that Bcl10 controls BAFF-induced canonical NF-κB activation directly and noncanonical 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.

Author List

Yu M, Chen Y, He Y, Podd A, Fu G, Wright JA, Kleiman E, Khan WN, Wen R, Wang D

Author

Demin Wang PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adaptor Proteins, Signal Transducing
Animals
Apoptosis
B-Cell Activating Factor
B-Cell CLL-Lymphoma 10 Protein
B-Lymphocytes
Cell Survival
Clonal Anergy
Gene Expression Regulation
I-kappa B Kinase
Mice
Mice, Transgenic
Muramidase
NF-kappa B
NF-kappa B p52 Subunit
Phosphorylation
Proto-Oncogene Proteins c-rel
Signal Transduction
Spleen
Transcription Factor RelB
bcl-X Protein
jenkins-FCD Prod-400 0f9a74600e4e79798f8fa6f545ea115f3dd948b2