The signaling subunits of the T-cell receptor and the B-cell receptor each contain ITAMs, which are essential for T-cell receptor and B-cell receptor signaling. Phosphorylation of both tyrosines in the ITAM functions to recruit a tyrosine kinase with tandem SH2 domains—ZAP-70 in the case of T cells, and a closely related kinase, Syk, in B cells. Other immune-system receptors also use ITAM-containing accessory chains to transduce activating signals (Fig. 7.14). One example is FcγRIII (CD16); this is a receptor for IgG that triggers anti-body-dependent cell-mediated cytotoxicity (ADCC) by NK cells, which we consider in Chapter 11; CD16 is also found on macrophages and neutrophils, where it facilitates the uptake and destruction of antibody-bound pathogens. To signal, FcγRIII must associate either with the ζchain found also in the T-cell receptor or with another member of the same protein family known as the Fcγ chain. The Fcγ chain is also the signaling component of another Fc receptor—the Fcε receptor I (FcεRI) on mast cells. As we discuss in Chapter 14, this receptor binds IgE antibodies, and on cross-linking by allergens, it triggers the degranulation of mast cells. Last, many activating receptors on NK cells are associated with DAP12, another ITAM-containing protein (see Section 3-26). Each of these additional ITAM-containing signaling chains becomes tyrosine phosphorylated following stimulation of its associated receptor, leading to the recruitment of a tyrosine kinase, either Syk or ZAP-70. With the exception of
Fig. 7.14 Other receptors that pair with ITAM-containing chains can deliver activating signals. cells other than B and T cells have receptors that pair with accessory chains containing iTams, which are phosphorylated when the receptor is cross-linked. These receptors deliver activating signals. The fcγ receptor iii (fcγRiii, or cd16) is found on nK cells, macrophages, and neutrophils. Binding of igG to this receptor activates the killing function of the nK cell, leading to the process known as antibody-dependent cell-mediated cytotoxicity (adcc). activating receptors on nK cells, such as nKG2c, nKG2d, and nKG2e, also associate with iTam-containing signaling chains. The fcε receptor (fcεRi) is found on mast cells and basophils. The α subunit binds to ige antibodies with very high affinity. The β subunit is a four-spanning transmembrane protein. When antigen subsequently binds to the ige, the mast cell is triggered to release granules containing inflammatory mediators. The γ chain associated with the fc receptors, and the dap12 chain that associates with the nK killer-activating receptors, also contain one iTam per chain and are present as homodimers.
T cells, Syk is broadly expressed in all leukocyte subsets; in contrast, ZAP-70 has been found only in T cells and NK cells.
Several viral pathogens seem to have acquired ITAM-containing receptors from their hosts. These include the Epstein–Barr virus (EBV), whose LMP2A gene encodes a membrane protein with a cytoplasmic tail containing an ITAM. This enables EBV to trigger B-cell proliferation by the signaling pathways discussed in Section 7-20, an important step in the development of EBV-induced malignancies. Another virus that expresses an ITAM-containing protein is the Kaposi sarcoma herpesvirus (KSHV or HHV8), which causes malignant transformation and proliferation of the cells it infects.
7-12 Activated ZAP-70 phosphorylates scaffold proteins and promotes PI 3-kinase activation.