Impaired Precursor B Cell Differentiation in Bruton's Tyrosine Kinase-Deficient Mice

• Published in: The Journal of immunology (1950) Vol. 168; no. 6; pp. 2695 - 2703
• Main Authors: Middendorp, Sabine, Dingjan, Gemma M, Hendriks, Rudolf W
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15-03-2002
• Subjects: Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia - genetics; Agammaglobulinemia - immunology; Agammaglobulinemia - pathology; Animals; Antigens, Differentiation, B-Lymphocyte - biosynthesis; Antigens, Differentiation, B-Lymphocyte - genetics; B-Lymphocyte Subsets - enzymology; B-Lymphocyte Subsets - immunology; B-Lymphocyte Subsets - pathology; Bone Marrow Cells - enzymology; Bone Marrow Cells - immunology; Bone Marrow Cells - pathology; Bruton's tyrosine kinase; CD2 antigen; CD25 antigen; Cell Cycle - genetics; Cell Cycle - immunology; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Division - genetics; Cell Division - immunology; Cells, Cultured; Cytoplasm - enzymology; Cytoplasm - immunology; Hematopoietic Stem Cells - enzymology; Hematopoietic Stem Cells - immunology; Hematopoietic Stem Cells - pathology; Immunoglobulin Heavy Chains - biosynthesis; Immunoglobulin Heavy Chains - genetics; Immunoglobulin mu-Chains - biosynthesis; Immunoglobulin mu-Chains - genetics; Immunophenotyping; Interleukin-7 - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout - genetics; Mice, Knockout - immunology; Protein-Tyrosine Kinases - biosynthesis; Protein-Tyrosine Kinases - deficiency; Protein-Tyrosine Kinases - genetics
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.168.6.2695

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.