Bruton's tyrosine kinase mediates NF-κB activation and B cell survival by B cell-activating factor receptor of the TNF-R family

Nicholas P. Shinners, Gianluca Carlesso, Iris Castro, Kristen L. Hoek, Radiah A. Corn, Robert L. Woodland, Martin L. Scott, Demin Wang, Wasif N. Khan

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

Loss of Bruton's tyrosine kinase (Btk) function results in mouse Xid disease characterized by a reduction in mature B cells and impaired humoral immune responses. These defects have been mainly attributed to impaired BCR signaling including reduced activation of the classical NF-κB pathway. In this study we show that Btk also couples the receptor for B cell-activating factor (BAFF) of the TNF family (BAFF-R) to the NF-κB pathway. Loss of Btk results in defective BAFF-mediated activation of both classical and alternative NF-κB pathways. Btk appears to regulate directly the classical pathway in response to BAFF such that Btk-deficient B cells exhibit reduced kinase activity of IκB kinase γ-containing complexes and defective IκBα degradation. In addition, Btk-deficient B cells produce reduced levels of NF-κB2 (p100) basally and in response to stimulation via the BCR or BAFF-R, resulting in impaired activation of the alternative NF-κB pathway by BAFF. These results suggest that Btk regulates B cell survival by directly regulating the classical NF-κB pathway under both BCR and BAFF-R, as well as by inducing the expression of the components of alternative pathway for sustained NF-κB activation in response BAFF. Thus, impaired BCR- and BAFF-induced signaling to NF-κB may contribute to the observed defects in B cell survival and humoral immune responses in Btk-deficient mice.

Original languageEnglish (US)
Pages (from-to)3872-3880
Number of pages9
JournalJournal of Immunology
Volume179
Issue number6
DOIs
StatePublished - Sep 15 2007
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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