Bruton’s Tyrosine Kinase Regulates the Activation of Gene Rearrangements at the l 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 z 50% reduction in the frequency of immunoglobulin (Ig) l 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 l usage. As the k / l ratio is dependent on (a) the level and kinetics of k and l 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 l usage. Crossing 3-83 md autoantibody transgenic mice into Btk-deficient mice showed that Btk is not essential for receptor editing. Also, Btkdeficient surface Ig 1 B cells that were generated in vitro in interleukin 7-driven bone marrow cultures manifested reduced l usage. An intrinsic defect in l locus recombination was further supported by the finding in Btk-deficient mice of reduced l 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 l locus for V(D)J recombination in pre-B cells.