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 similar to 50% reduction in the frequency of immunoglobulin (Ig) h 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 K and h 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 X usage. Crossing 3-83 mu delta autoantibody transgenic mice into Btk-deticient 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 h usage. An intrinsic defect in X locus recombination was further supported by the finding in Btk-deficient mice of reduced h 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 X locus for V(D)J recombination in pre-B cells.