Figure 2.

How NK cells contributed to our idea of “inhibition” in the immune system. Inhibition in immune cells is based on the presence of ITIM-containing molecules and in the recruitment of SH2 domain-containing protein phosphatases. Although the presence of an ITIM sequence may represent a basic operation mode for inhibition, there are important differences in how signals are displayed downstream ITIM phosphorylation. For simplicity, only two major systems of inhibition are depicted. (A) The FcγRIIB receptor binds a single-SH2 domain-containing phosphatidylinositol 5-phosphate (SHIP1). Activation of SHIP-1 leads to dephosphorylate various substrates downstream ITAM-containing receptors. FcγRIIB coaggregation with activating receptors is mandatory to allow Src family kinases to phosphorylate both, the ITAMs and the ITIMs. (B) Inhibitory NK cell receptors bind a two-SH2 domain containing tyrosine phosphatase (SHP1/2). ITIM-containing NK cell receptors are constitutively associated with Src family kinases and as consequence they can signal independently of activating receptors ligation However, coaggregation of an inhibitory NK cell receptor with activating ITAM-containing receptors is necessary to inhibit cell activation. For ITIM-containing NK cell receptors, Vav1 seems to be the only signaling protein associated with the catalytic site of SHP-1 upon recognition of target cells expressing HLA molecules. Moreover, NK cell inhibitory receptors seem to operate no only by promoting tyrosine dephosphorylation, since they are also able to promote the tyrosine phosphorylation of the adapter protein Crk and to promote its association with the tyrosine kinase c-Abl.