Impaired precursor B cell differentiation in Bruton's tyrosine kinase-deficient mice.
Bruton's tyrosine kinase (Btk) is a cytoplasmic signaling molecule that is crucial for precursor (pre-B) cell differentiation in humans. In this study, we show that during the transition of large cycling to small resting pre-B cells in the mouse, Btk-deficient cells failed to efficiently modulate the expression of CD43, surrogate L chain, CD2, and CD25. In an analysis of the kinetics of pre-B cell differentiation in vivo, Btk-deficient cells manifested a specific developmental delay within the small pre-B cell compartment of about 3 h, when compared with wild-type cells. Likewise, in in vitro bone marrow cultures, Btk-deficient large cycling pre-B cells showed increased IL-7 mediated expansion and reduced developmental progression into noncycling CD2(+)CD25(+) surrogate L chain-negative small pre-B cells and subsequently into Ig-positive B cells. Furthermore, the absence of Btk resulted in increased proliferative responses to IL-7 in recombination-activating gene-1-deficient pro-B cells. These findings identify a novel role for Btk in the regulation of the differentiation stage-specific modulation of IL-7 responsiveness in pro-B and pre-B cells. Moreover, our results show that Btk is critical for an efficient transit through the small pre-B cell compartment, thereby regulating cell surface phenotype changes during the developmental progression of cytoplasmic mu H chain expressing pre-B cells into immature IgM(+) B cells.
Middendorp
Sabine
S
Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
Dingjan
Gemma M
GM
Hendriks
Rudolf W
RW
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis / Q000235:genetics; D016175:B-Lymphocyte Subsets / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003593:Cytoplasm / Q000201:enzymology / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D007148:Immunoglobulin mu-Chains / Q000096:biosynthesis / Q000235:genetics; D016130:Immunophenotyping; D015851:Interleukin-7 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*
D000944:Antigens, Differentiation, B-Lymphocyte; D007143:Immunoglobulin Heavy Chains; D007148:Immunoglobulin mu-Chains; D015851:Interleukin-7; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse