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© The Rockefeller University Press, 0022-1007/1997/10/1307/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 8, October 20, 1997 1307-1314

Articles

Negative Regulation of Fc{varepsilon}RI-mediated Degranulation by CD81

Tony J. Fleming, Emmanuel Donnadieu, Chang Ho Song, Francois Van Laethem, Stephen J. Galli, and Jean-Pierre Kinet

From the Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

Signaling through the high affinity receptor for immunoglobulin E (Fc{varepsilon}RI) results in the coordinate activation of tyrosine kinases before calcium mobilization. Receptors capable of interfering with the signaling of antigen receptors, such as Fc{varepsilon}RI, recruit tyrosine and inositol phosphatases that results in diminished calcium mobilization. Here, we show that antibodies recognizing CD81 inhibit Fc{varepsilon}RI-mediated mast cell degranulation but, surprisingly, without affecting aggregation-dependent tyrosine phosphorylation, calcium mobilization, or leukotriene synthesis. Furthermore, CD81 antibodies also inhibit mast cell degranulation in vivo as measured by reduced passive cutaneous anaphylaxis responses. These results reveal an unsuspected calcium-independent pathway of antigen receptor regulation, which is accessible to engagement by membrane proteins and on which novel therapeutic approaches to allergic diseases could be based.

Address all correspondence to Dr. Jean-Pierre Kinet, Department of Pathology, Laboratory of Allergy and Immunology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215. Phone: 617-667-1324; FAX: 617-667-3616; E-mail: jkinet{at}mercury.bidmc.harvard.edu. The present address of F. Van Laethem is Free University of Brussels, 1180 Brussels, Belgium.

1 Abbreviations used in this paper: DNP–HSA, DNP–human serum albumin; ER, endoplasmic reticulum; Fc{varepsilon}RI, high affinity receptor for IgE; Fc{gamma}RIIbl, low affinity receptor for IgG; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; KIR, killer cell inhibitory receptor; LTC4, leukotriene C4; PCA, passive cutaneous anaphylaxis; PTK, protein tyrosine kinase; RBL-2H3, rat basophilic leukemia cell line; SH, Src homology; SHIP, SH2-domain–containing polyphosphatidylinositol (3,4,5) 5' phosphatase; SHP-1/SHP-2, SH2-domain– containing phosphatase-1 or -2; TM4SF, transmembrane 4 superfamily.


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