Activating Receptors In Nk Cells

The receptors that initiate activation of NK cells recognize a wide variety of ligands, many of which are still unidentified. Unlike T cell receptors, which can bind to antigens only when they are presented in the context of self (in major histocompatibility complexes, or MHCs), activating receptors in NK cells can directly recognize viral peptides as well as ligands on target cells that indicate target cell stress. As a result, NK cells can contribute to the initial defense against viruses and infections, greatly increasing the ability of the immune system to recognize problems in cells early and to respond to them quickly.

Despite this recognition of different ligands, many of the activating receptors contain highly conserved ITAMs within the receptor complex. Located on the cytoplasmic side of the receptors, an ITAM consists of the peptide sequence YxxL(I)x YxxL(I) [3,4]. One or more of these sequences may be found in the cytoplasmic tails of the adapter proteins that are noncovalently associated with the ligand binding immune recognition receptors. Once the receptor is bound by its ligand, the tyrosine in the ITAM is phosphorylated by a Src family protein tyrosine kinase (e.g., Lck, Fyn). Following phosphorylation, the ITAMs recruit and activate the Syk family tyrosine kinases (e.g., Syk, ZAP-70) through their SH2 domains [reviewed in 5], Once activated, the Syk family tyrosine kinases are able to interact with adapter proteins and initiate the activation of a host of second messengers (Fig. 2).

The adapter proteins associated with activating receptors in NK cells are CD3<^, FceRIy, and DAP12. To date, signaling pathways have not been completely traced from each receptor to the corresponding effector mechanism (e.g., granule exocytosis, cell-mediated cytotoxicity, and transcriptional regulation), but various pathways are known to be required for activation of particular effector mechanisms. By using pharmacologic inhibitors and genetic manipulation of effector cells, researchers have been able to determine many of the components of signaling pathways necessary for different types of activation. This work has provided insights into what is needed to activate and regulate different pathways, leading to an emerging understanding of the roles of different receptors in activating NK cells and the rest of the immune system. Next we briefly discuss the roles of several activating receptors.

3.1. FcyRIII

The human receptor involved in ADCC, FcyRIII, is a multimeric receptor complex consisting of the ligand-binding receptor CD 16 (a subunit) which associates non-covalently with the ITAM-containing homodimers or heterodimers of C, or y [6-9]. The signaling of this receptor through ITAMs is very similar to that of the T cell receptor (TCR) on T lymphocytes. As in TCR signaling, after ligand binding, Src family kinases bind and phosphorylate tyrosine residues in the ITAMs. These phosphorylated tyrosines recruit Syk family protein tyrosine kinases

Ugand binding receptor ¿

ITAM-containing subunits

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