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 (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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7 September 1998
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September 07 1998
Independent and Opposing Roles For Btk and Lyn in B and Myeloid Signaling Pathways
Anne B. Satterthwaite,
Anne B. Satterthwaite
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
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Clifford A. Lowell,
Clifford A. Lowell
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
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Wasif N. Khan,
Wasif N. Khan
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
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Paschalis Sideras,
Paschalis Sideras
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
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Frederick W. Alt,
Frederick W. Alt
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
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Owen N. Witte
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
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Anne B. Satterthwaite
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
Clifford A. Lowell
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
Wasif N. Khan
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
Paschalis Sideras
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
Frederick W. Alt
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
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
Address correspondence to Owen N. Witte, 5-748 MacDonald Research Laboratories, 675 Circle Dr. South, Los Angeles, CA 90095-1662. Phone: 310-206-6411; Fax: 310-206-8822; E-mail: [email protected]
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.
Received:
March 06 1998
Revision Received:
April 22 1998
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 188 (5): 833–844.
Article history
Received:
March 06 1998
Revision Received:
April 22 1998
Citation
Anne B. Satterthwaite, Clifford A. Lowell, Wasif N. Khan, Paschalis Sideras, Frederick W. Alt, Owen N. Witte; Independent and Opposing Roles For Btk and Lyn in B and Myeloid Signaling Pathways . J Exp Med 7 September 1998; 188 (5): 833–844. doi: https://doi.org/10.1084/jem.188.5.833
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