Fc gamma RIIB-mediated inhibition of T-cell receptor signal transduction involves the phosphorylation of SH2-containing inositol 5-phosphatase (SHIP), dephosphorylation of the linker of activated T-cells (LAT) and inhibitionof calcium mobilization

The low-affinity receptor for immunoglobulin G, Fc gamma RIIB, is expressed on most B-cells and on immature and activated mature T-cells. Coaggregatio n of Fc gamma RIIB with the B-cell antigen receptor (BCR) leads to attenuat ion of BCR-induced blastogenesis and cell proliferation via inhibition of p 21(ras), phosphatidylinositol 3-kinase (PI3-K) and phospholipase C gamma (P LC gamma) activation. These effects are mediated, at least in part, by the recruitment of SH2-containing protein tyrosine phosphatase-1 (SHP-1) and -2 (SHP-2) and SH2-containing inositol 5-phosphatase (SH IP). In this report, we demonstrate that Fc gamma RIIB coaggregation with the T-cell antigen re ceptor (TCR), which may occur when T-cells recognize antibody-coated target cells, leads to inhibition of TCR-induced phosphorylation of the linker of activated T-cells (LAT). When phosphorylated, LAT functions as an adapter molecule and recruits PI3-K. Additionally, we demonstrate that PI3-K is req uired for TCR-induced Ca2+ mobilization. Together, these data suggest that Fc gamma RIIB may inhibit TCR-mediated Ca2+ mobilization, in part via inhib ition of LAT phosphorylation and subsequent inhibition of PI3-K activation. A similar mechanism has been described in B-cells, where Fc gamma RIIB co- aggregation with the BCR leads to inhibition of PI3-K activity via dephosph orylation of CD19. It is likely that, in both cell types, levels of PtdIns( 3,4,5)P-3 are additionally modulated via the enzymic activity of SHIP.