15353-j-veluchamy

1 General introduction and Scope of this Thesis | 9 Natural killer cells and their activating and inhibitory receptors Human NK cells are generally categorized by their level of CD56 and CD16 expression into two subsets: CD56 bright CD16 dim and CD56 dim CD16 bright NK cells. Most NK cells in the peripheral blood and spleen are CD56 dim CD16 bright and are cytotoxic against a variety of tumor cells, whereas CD56 bright CD16 dim NK cells are immune regulatory in function and constitute the majority of NK cells in secondary lymphoid tissues, producing abundant cytokines but exerting weak cytotoxicity compared to CD56 dim CD16 bright NK cells 9 . The ability of NK cells to discriminate between a cancer cell and a healthy cell is regulated by a balance between activating and inhibitory receptors. NK activating receptors like DNAM-1, NKG2D, Natural Cytotoxicity Receptors (NCRs) NKp30, NKp44, NKp46, CD94/NKG2C, CD94/NKG2E, CD16a and activating killer cell-immunoglobulin like receptors (KIRs) contribute to NK cell activation, triggering the release of cytotoxic granules and pro-inflammatory cytokines such as interferon-gamma (IFNγ) to fight cancer cells 10 . The NK cell activating receptor NKG2D (CD314) recognizes MHC class-I-chain related protein A and B (MICA and MICB) and ULBPs (1-6) 11 , while DNAM-1 binds to CD112 (Nectin-2) and CD155 (poliovirus receptor) 12 on stressed, infected, and cancer cells. The ligands for NCRs are widely expressed on cells infected by viruses or by intracellular bacteria and on tumor cells, but their exact modes of action and roles in NK cytotoxicity are yet to be characterized 13 . In addition to this, the heterodimers of the NKG2 family; CD94/NKG2C and CD94/NKG2E recognize the non- classical MHC class I molecule HLA-E and associate with DAP-12 molecule to trigger an NK activation signal 14,15 . Another very important activation mechanism of NK cells is through the interaction of CD16a (FcγRIIIa, a low affinity Fc receptor) with the Fc portion of IgG 1 antibodies, forming an immunological synapse to engage antibody opsonized targets for NK cell mediated antibody dependent cell mediated cytotoxicity (ADCC) 16 . In addition to this, NK cells can also lyse tumor targets using Tumor Necrosis Factor α (TNF-α), Fas ligand and TNF-related apoptosis-inducing ligand (TRAIL) 17 . The most prominent NK cell inhibitory receptors include inhibitory KIRs that recognize MHC class I (HLA-ABC) molecules, which are expressed on healthy tissues. Similarly, CD94/NKG2A, an inhibitory receptor from the NKG2 family, binds to HLA-E and induces NK cell tolerance through the activation of an intracellular immunoreceptor tyrosine-based inhibitory motif (ITIMs) 15 . Hence, knowing that NK cell functions are determined by an array of receptors, which can transmit either an activating or an inhibitory signal, depending on different ligand interactions on the surface of tumor cells, it is critical to shift the balance in a therapeutic setting towards an activating NK phenotype to expedite enhanced NK tumor killing mechanisms (Figure 1). NK cell dysfunctionality in cancer NK cells can control circulating tumor cells and prevent formation of tumor metastases 18 . However, tumors employ different strategies to evade killing by NK cells. Up-regulation of