Negative regulation of Fc epsilon RI-mediated degranulation by CD81

Signaling through the high affinity receptor for immunoglobulin E (Fc epsilon 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 epsilon RI, recruit tyrosine and inositol phosphatases that results in diminished calcium mobilization. Here, we show that antibodies recognizing CD81 inhibit Fc epsilon 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.