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

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-kappa B 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-kappa B pathway. Loss of Btk results in defective BAFF-mediated activation of both classical and alternative NF-kappa B pathways. Btk appears to regulate directly the classical pathway in response to BAFF such that Btk-deficient B cells exhibit reduced kinase activity of I kappa B kinase gamma-containing complexes and defective I kappa B alpha degradation. In addition, Btk-deficient B cells produce reduced levels of NF-kappa B2 (p100) basally and in response to stimulation via the BCR or BAFF-R, resulting in impaired activation of the alternative NF-kappa B pathway by BAFF. These results suggest that Btk regulates B cell survival by directly regulating the classical NF-kappa B pathway under both BCR and BAFF-R, as well as by inducing the expression of the components of alternative pathway for sustained NF-kappa B activation in response BAFF. Thus, impaired BCR- and BAFF-induced signaling to NF-kappa B may contribute to the observed defects in B cell survival and humoral immune responses in Btk-deficient mice.