Bruton's tyrosine kinase mediates NF-kappa B 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-kappaB 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-kappaB pathway. Loss of Btk results in defective BAFF-mediated activation of both classical and alternative NF-kappaB pathways. Btk appears to regulate directly the classical pathway in response to BAFF such that Btk-deficient B cells exhibit reduced kinase activity of IkappaB kinase gamma-containing complexes and defective IkappaBalpha degradation. In addition, Btk-deficient B cells produce reduced levels of NF-kappaB2 (p100) basally and in response to stimulation via the BCR or BAFF-R, resulting in impaired activation of the alternative NF-kappaB pathway by BAFF. These results suggest that Btk regulates B cell survival by directly regulating the classical NF-kappaB pathway under both BCR and BAFF-R, as well as by inducing the expression of the components of alternative pathway for sustained NF-kappaB activation in response BAFF. Thus, impaired BCR- and BAFF-induced signaling to NF-kappaB may contribute to the observed defects in B cell survival and humoral immune responses in Btk-deficient mice.
Shinners
Nicholas P
NP
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA.
Carlesso
Gianluca
G
Castro
Iris
I
Hoek
Kristen L
KL
Corn
Radiah A
RA
Woodland
Robert T
RT
Woodland
Robert L
RL
Scott
Martin L
ML
Wang
Demin
D
Khan
Wasif N
WN
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D053265:B-Cell Activation Factor Receptor / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D001402:B-Lymphocytes / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology