FcyRIIB-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 inhibition of calcium mobilization

T h e low-affinity receptor for immunoglobulin G , FcyRIIB, is expressed on most B-cells and on immature and activated mature T-cells. Coaggregation of FcyRIIB with the B-cell antigen receptor (BCR) leads to attenuation of BCRinduced blastogenesis and cell proliferation via inhibition of p21'*', phosphatidylinositol 3-kinase (PI3-K) and phospholipase Cy (PLCy) 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 (SHIP). In this report, we demonstrate that FcyRIIB coaggregation with the T-cell antigen receptor (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 P13-K. Additionally, we demonstrate that PI3-K is required for TCR-induced Ca2' mobilization. Together, these data suggest that FcyRIIB may inhibit TCR-mediated Cay+ mobilization, in part via inhibition of LAT phosphorylation and subsequent inhibition of PI3-K activation. A similar mechanism has been described in B-cells, where FcyRIIB co-aggregation with the BCR leads to inhibition of PI3-K activity via dephosphorylation of CD19. I t is likely that, in both cell types, levels of PtdIns(3,4,5)P3 are additionally modulated via the enzymic activity of SHIP.