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B Activation and B Cell Survival by B Cell-Activating Factor Receptor of the TNF-R Family1
* Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232-0146;
Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655-0002;
Biogen Idec, Cambridge, MA 02142; and
The Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226
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-
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-B pathway. Loss of Btk results in defective BAFF-mediated activation of both classical and alternative NF-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 IB kinase 
-containing complexes and defective IB
degradation. In addition, Btk-deficient B cells produce reduced levels of NF-B2 (p100) basally and in response to stimulation via the BCR or BAFF-R, resulting in impaired activation of the alternative NF-B pathway by BAFF. These results suggest that Btk regulates B cell survival by directly regulating the classical NF-B pathway under both BCR and BAFF-R, as well as by inducing the expression of the components of alternative pathway for sustained NF-B activation in response BAFF. Thus, impaired BCR- and BAFF-induced signaling to NF-B may contribute to the observed defects in B cell survival and humoral immune responses in Btk-deficient mice.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study is supported in part by Grants RO1 AI50213-01 and AI060729-01 (to W.N.K.) and R01 HL073284 (to D.W.) from the National Institutes of Health and by Grants RSG TBE-102299 (to W.N.K.) and RSG CCG-106204 (to D.W.) from the American Cancer Society. N.P.S. and K.H. are supported by Grant T32 HL69715-0 (to J. Hawiger) and I.C. is supported by Grant T32 CA09385-20 (to H. E. Ruley) from the National Institutes of Health.
2 N.P.S. and G.C. contributed equally to this study.
3 Address correspondence and reprint requests to Dr. Wasif N. Khan, Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232-0146. E-mail address: Wasif.Khan{at}vanderbilt.edu
4 Abbreviations used in this paper: Btk, Bruton’s tyrosine kinase; BAFF, B cell-activating factor; PLC, phospholipase C; wt, wild type; IKK, IB kinase; TACI, transmembrane activator and cyclophilin ligand interactor; RIPA, radioimmunoprecipitation assay; PKC, protein kinase C.
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