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J. Exp. Med.,
Volume 187, Number 8, April 20, 1998 1235-1247
RI-dependent
Mast Cell Degranulation and Cytokine Production
By
From the * Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California
92121; the We investigated the role of Bruton's tyrosine kinase (Btk) in Fc Department of Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi,
Gifu 502, Japan; the § Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard
Medical School, Boston, Massachusetts 02115; the Department of Hematopoietic Factors, Institute of
Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan; the ¶ Howard Hughes Medical Institute, Children's Hospital, Enders 861, Boston, Massachusetts 02115;
the ** Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the Howard Hughes
Medical Institute, University of California, Los Angeles, California 90024-1662
RI-dependent activation of
mouse mast cells, using xid and btk null mutant mice. Unlike B cell development, mast cell development is apparently normal in these btk mutant mice. However, mast cells derived from
these mice exhibited significant abnormalities in FcRI-dependent function. xid mice primed
with anti-dinitrophenyl monoclonal IgE antibody exhibited mildly diminished early-phase and
severely blunted late-phase anaphylactic reactions in response to antigen challenge in vivo.
Consistent with this finding, cultured mast cells derived from the bone marrow cells of xid or
btk null mice exhibited mild impairments in degranulation, and more profound defects in the
production of several cytokines, upon FcRI cross-linking. Moreover, the transcriptional activities of these cytokine genes were severely reduced in FcRI-stimulated btk mutant mast
cells. The specificity of these effects of btk mutations was confirmed by the improvement in the
ability of btk mutant mast cells to degranulate and to secrete cytokines after the retroviral transfer of wild-type btk cDNA, but not of vector or kinase-dead btk cDNA. Retroviral transfer of
Emt (= Itk/Tsk), Btk's closest relative, also partially improved the ability of btk mutant mast
cells to secrete mediators. Taken together, these results demonstrate an important role for Btk
in the full expression of FcRI signal transduction in mast cells.
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