Transphosphorylation by Src family kinases is required for the activation of 
Bruton's tyrosine kinase (Btk). Differences in the phenotypes of Btk-/- and 
lyn-/- mice suggest that these kinases may also have independent or opposing 
functions. B cell development and function were examined in Btk-/-lyn-/- mice to 
better understand the functional interaction of Btk and Lyn in vivo. The 
antigen-independent phase of B lymphopoiesis was normal in Btk-/-lyn-/- mice. 
However, Btk-/-lyn-/- animals had a more severe immunodeficiency than Btk-/- 
mice. B cell numbers and response to T cell-dependent antigens were reduced. Btk 
and Lyn therefore play independent or partially redundant roles in the 
maintenance and function of peripheral B cells. Autoimmunity, hypersensitivity 
to B cell receptor (BCR) cross-linking, and splenomegaly caused by 
myeloerythroid hyperplasia were alleviated by Btk deficiency in lyn-/- mice. A 
transgene expressing Btk at approximately 25% of endogenous levels (Btklo) was 
crossed onto Btk-/- and Btk-/-lyn-/- backgrounds to demonstrate that Btk is 
limiting for BCR signaling in the presence but not in the absence of Lyn. These 
observations indicate that the net outcome of Lyn function in vivo is to inhibit 
Btk-dependent pathways in B and myeloid cells, and that Btklo mice are a useful 
sensitized system to identify regulatory components of Btk signaling pathways.