Bruton's tyrosine kinase regulates the activation of gene rearrangements at the lambda light chain locus in precursor B cells in the mouse.
Bruton's tyrosine kinase (Btk) is a nonreceptor tyrosine kinase involved in precursor B (pre-B) cell receptor signaling. Here we demonstrate that Btk-deficient mice have an approximately 50% reduction in the frequency of immunoglobulin (Ig) lambda light chain expression, already at the immature B cell stage in the bone marrow. Conversely, transgenic mice expressing the activated mutant Btk(E41K) showed increased lambda usage. As the kappa/lambda ratio is dependent on (a) the level and kinetics of kappa and lambda locus activation, (b) the life span of pre-B cells, and (c) the extent of receptor editing, we analyzed the role of Btk in these processes. Enforced expression of the Bcl-2 apoptosis inhibitor did not alter the Btk dependence of lambda usage. Crossing 3-83mudelta autoantibody transgenic mice into Btk-deficient mice showed that Btk is not essential for receptor editing. Also, Btk-deficient surface Ig(+) B cells that were generated in vitro in interleukin 7-driven bone marrow cultures manifested reduced lambda usage. An intrinsic defect in lambda locus recombination was further supported by the finding in Btk-deficient mice of reduced lambda usage in the fraction of pre-B cells that express light chains in their cytoplasm. These results implicate Btk in the regulation of the activation of the lambda locus for V(D)J recombination in pre-B cells.
Dingjan
G M
GM
Department of Immunology, Faculty of Medicine, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands.
Middendorp
S
S
Dahlenborg
K
K
Maas
A
A
Grosveld
F
F
Hendriks
R W
RW
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D018941:Antigens, CD19; D001402:B-Lymphocytes / Q000276:immunology*; D001854:Bone Marrow Cells; D004789:Enzyme Activation; D005260:Female; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D019254:Genes, bcl-2; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017393:RNA Editing; D011947:Receptors, Antigen, B-Cell / Q000235:genetics
D018941:Antigens, CD19; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse