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J. Exp. Med.,
Volume 188, Number 5, September 7, 1998 833-844
By
From the * Department of Microbiology and Molecular Genetics, University of California Los Angeles,
Los Angeles, California 90095; the Transphosphorylation by Src family kinases is required for the activation of Bruton's tyrosine
kinase (Btk). Differences in the phenotypes of Btk Department of Laboratory Medicine, University of California
San Francisco, San Francisco, California 94143; the § Howard Hughes Medical Institute, The
Children's Hospital, Boston, Massachusetts 02115; the Unit of Applied Cell and Molecular Biology,
Umea University, S-901 87 Umea, Sweden; and the ¶ Howard Hughes Medical Institute, University
of California Los Angeles, Los Angeles, California 90095
/ 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 (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.
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