Abstract
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 ∼25% of endogenous levels (Btk
lo
) 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 Btk
lo
mice are a useful sensitized system to identify regulatory components of Btk signaling pathways.
