Double knockout mice show BASH and PKCdelta have different epistatic relationships in B cell maturation and CD40-mediated activation.
The development and survival of mature B cells requires an antigen-independent signal from the B cell receptor (BCR) through an adaptor protein containing an SH2 domain, BASH (BLNK/SLP-65). It also requires signaling through BAFF and the BAFF receptor (BAFF-R), and is negatively regulated by protein kinase Cdelta (PKCdelta). In PKCdelta-deficient mice, B cell maturation occurs independently of the BAFF receptor (BAFF-R), indicating that BAFF-R signaling promotes maturation by inhibiting the negative function of PKCdelta. To clarify which of the two signaling pathways plays the primary role in B cell maturation, we crossed BASH-deficient mice with PKCdelta-deficient mice to generate BASH/PKCdelta-double knockout (DKO) mice. In the DKO mice, B cell maturation was blocked at the transitional type 1 (T1) stage and B cells were prone to apoptosis, in common with BASH-deficient mice. This indicates that BASH-mediated BCR signaling primarily controls B cell survival and maturation, with BAFF-R signaling and its inhibition of PKCdelta acting as a secondary regulator. By contrast, CD40-mediated proliferation and antibody production, which are low in BASH-deficient mice, were rescued in the DKO mice, indicating that the suppression of CD40-mediated B cell activation by PKCdelta is epistatic to BASH-mediated promotion. The physiological relevance of these opposing hierarchical effects of BASH and PKCdelta in the regulation of B cell maturation and activation is discussed.
Nojima
Takuya
T
Division of Molecular Biology, Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan.
Hayashi
Katsuhiko
K
Goitsuka
Ryo
R
Nakayama
Keiko
K
Nakayama
Keiichi
K
Kitamura
Daisuke
D
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation; D004843:Epistasis, Genetic; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D051745:Protein Kinase C-delta / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D019013:CD40 Antigens; D002352:Carrier Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D018124:Receptors, Tumor Necrosis Factor; C486662:Tnfrsf13c protein, mouse; C505720:Tnfsf13b protein, mouse; D014409:Tumor Necrosis Factor-alpha; C497259:Prkcd protein, mouse; D051745:Protein Kinase C-delta