J

Granule exocytosis, cell-mediated cytotoxicity, transcriptional regulation, apoptosis

Figure 2. Signals from activating rcceplors containing ITAM&. Upon ligand binding to an ITAM-containing activating receptofi Sic family kinases phosphorylale tyrosines in ihc ITAM. The phosphorylated ITAMs then recruit and activate the Syk family protein tyrosine kinases (Syk, ZAP-70J through their SI12 domains. Once activated, ZAP-7G and Syk recruit adaptors such as LAT and signalling molecules sueh as PI3K. The activation of major signalling pathways such as the MAPK, PI3K and PLCy pathways along with activation of the Rho/Rac GTPases insults in the activation of the NK cell and drives its effector functions.

through (heir SH2 domains, resulting in the phosphorylation and activation oi' the Syk family protein tyrosine kinases [10,1! 1 to initiate downstream signaling ihrough a variety of intracellular signaling molecules including activation of ptiospholipase (PLC)-"/ 112,13], This results in increased intracellular Ca2+ concentration, increased p h os pha t i d y 1 i n os i t o 1 - 3 - k i n a sc (PI3K) activity [14,15], increased activity of the Rho/Rac GTPases ¡16,17!, aTitl stimulation of the MAP kinase pathway [18].

Although there are many similarities, signaling through FcyRlIl is not identical to signaling from a TCR. For example, while the tyrosine phosphatase CD45 is crucial for T cell activation, CD45-deficient mice exhibit functional killing mediated by ADCC 119]. Moreover, mice with double knockouts ofSrc-family tyrosine kinases (Lck and Fyn). the first and crucial kinases activated after T cell engagement, have inlact ADCC in NK cells [20]. These differences in signal transduction highlight the need to recognize (he unique features of NK cell signaling in order to understand (he differential regulation of separate subpopulations of lymphocytes and in order to develop drugs lo specifically large! disiinct aspects of the immune system.

3.2. NKp30 and NKp46

The natural cytotoxicity receptors NKp30 and NKp46 are believed to initiate cytotoxicity upon binding to tumour cells [21,22]. NKp46 is also known to recognize hemagglutinins on virally infected cells [23], and it is involved in NK cell-mediated lysis of cells infected with an intracellular pathogen [24]. In humans, these receptors associate with ITAM-containing CD3(^-homodimers. NKp46 can also associate with ITAM-containing FceRIy-CD3^ heterodimers. Both of these types of ITAMs are phosphorylated by Src family tyrosine kinases, which recruit Syk and ZAP70 in a conventional manner. Cross-linking of NKp46 by antibodies drives an increase in intracellular calcium, cytokine production, and cytotoxic activity [25]. Identification of other ligands of NKp46 and NKp30 will serve to further elucidate how NK cells are activated and whether signals from different ligands to the same receptor vary.

3.3. NKp44 and KIR2DS2

The activating receptor NKp44 is expressed only on IL-2 activated NK cells [26]. Like NKp46, NKp44 can recognize hemagglutinins on virally infected cells [27]. NKp44 is known to be triggered during tumour cell lysis, and it is possible that it may recognize tumour-associated ligands [26]. This receptor associates with homodimers of the ITAM-containing adapter protein DAP 12 (also known as KARAP), and this association is necessary for surface expression of NKp44 [28]. Once phosphorylated, DAP12 peptides bind ZAP70 and Syk protein tyrosine kinases [29].

The proposed physiological ligand for the activating receptor 2B4 is CD48, a glycosyl-phos-phatidyl-inositol (GPI)-anchored cell surface protein [30,31], Upon binding to CD48 or when crosslinked with antibodies, 2B4 initiates increased cytotoxicity and cytokine secretion [32], 2B4 itself does not, however, associate with any ITAM-containing polypeptides. Rather, it contains four TxYxxV(I) motifs that upon ligand binding are phosphorylated. Once phosphorylated, the motifs associate with the adaptor protein SAP and the p85 regulatory subunit of PI3K [33,34], The phosphorylated TxYxxV(I) motifs may also bind via SH2 domains to the phosphatase SHP-2 or the adapter protein LAT [35]. Despite its lack of ability to activate protein tyrosine kinases through the ITAM pathway, 2B4 appears to play a role as a co-receptor by modulating other receptor-ligand interactions [36], The possibility remains, however, that 2B4 may have the ability to independently activate NK cell functions.

3.5. NKG2D

The activating receptor NKG2D binds to the target cell ligands MICA [37] and MICB and the ULBP proteins [38,39] in humans and to H60, Rae-1, and MULT1 in mice [40-421. The proteins MICA, MICB, H60, Rae-1, and MULT1 are stress-inducible molecules rarely expressed on normal cells. These proteins are highly expressed on certain types of tumours. ULBP proteins are, like MICA and MICB, distant members of the MHC class I family of proteins, but they are not believed to be able to present antigen. They are thought to play a role in fighting human cytomegalovirus (CMV), and one CMV protein can even block the ULBP-NKG2D association [39,43]. NKG2D-mediated binding to any of these ligands on target cells can then initiate activation of the NK cells and cytotoxicity.

NKG2D associates with the non-ITAM-containing adapter DAP 10 [44]. DAP 10 contains a YxxM motif that is phosphorylated by Src family protein tyrosine kinases but does not recruit Syk family tyrosine kinases. Once phosphorylated, the YxxM motif can recruit PI3K directly through the SH2 domain of its p85 regulatory subunit. This alternative method of activation provides a means for costimulation with ITAM-containing receptors [45]. Recent reports suggest that alternatively spliced forms of NKG2D may also associate in mice with the ITAM-con-taining adapter DAP 12, allowing the receptor to act in an activating as well as a costimulatory fashion [46,47],

3.6. Activating receptors in the KIR and Ly49 families

The extracellular portions of some activating receptors are structurally similar to the extracellular portions of inhibitory receptors (killer cell Ig-like receptors, or KIRs, in humans and Ly49 in mice) and so are said to be in the same family despite their differences in function. These activating receptors have short cytoplasmic tails that do not contain an ITIM. Instead, these shortened receptors have a positively charged lysine residue in their transmembrane domain that allows them to interact with the ITAM-containing DAP 12; thus, ligand binding results in cellular activation [29]. While the inhibitory receptors have high affinity for self MHC class I, the activating receptors have a decreased affinity for self and an increased affinity for specific class I-like molecules. For example, an activating isoform of Ly49 can recognize an MHC class I-like CMV protein [48]. This ability to recognize self-like proteins suggests that these activating isoforms may arise as a result of selective pressure imposed by pathogens.

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