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Articles

Anne B. Satterthwaite^*, Clifford A. Lowell, Wasif N. Khan, Paschalis Sideras^||, Frederick W. Alt, and Owen N. Witte^*,¶

From the ^* Department of Microbiology and Molecular Genetics, University of California Los Angeles, Los Angeles, California 90095; the 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

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.

Key Words: B cell receptor • B cell development • Src family kinases • transgenic mice • immunodeficiency

Anne Satterthwaite was supported by a postdoctoral fellowship from the Irvington Institute for Immunological Research. Paschalis Sideras is supported by the Swedish Medical Research Council (MFR). Owen Witte and Frederick Alt are Investigators of the Howard Hughes Medical Institute. This work was partially funded by a US Public Health Service grant (CA-12800; Principal Investigator Randy Wall).

Wasif Khan's current address is Department of Microbiology and Immunology, School of Medicine, Vanderbilt University, Nashville, TN 37232-2363.

Abbreviations used: ALPH, alkaline phosphatase; BBS, borate-buffered saline; BCR, B cell antigen receptor; BrdU, bromodeoxyuridine; Btk, Bruton's tyrosine kinase; Btk^lo, mice lacking the endogenous Btk gene and expressing 25% of endogenous levels of Btk in B cells from an Ig heavy chain enhancer/promoter–driven transgene; KLH, keyhole limpet hemocyanin; TNP, 2,4,6-trinitrophenyl; me, motheaten; wt, wild-type; xid, X-linked immunodeficiency; XLA, X-linked agammaglobulinemia.

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