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Immune response CD16 signaling in NK cells

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Immune response CD16 signaling in NK cells

CD16 signaling in NK cells

Natural killer (NK) cells mediate antibody-depend cellular cytotoxicity through the Fcfragment of IgG, low affinity IIIa and receptor (CD16a) ( Fc gamma RIII alpha(CD16) ) [1], [2]. The preferred ligands for Fc gammaRIII alpha (CD16) on NK cells are Immunoglobulins gamma 1 and 3 ( IgG1 andIgG3 ) [3], [4]. Fc gamma RIII alpha (CD16)covalently associates with the Membrane-bound signaling adaptor CD247 molecule ( CD3zeta ), which transduces signal to cytoplasm [5], [6]. Uponligand binding and receptor activation, CD3 zeta is phosphorilated byLymphocyte-specific protein tyrosine kinase ( Lck ) [7]and Zeta-chain associated protein kinase 70kDa ( ZAP70 ) [8], [9].

Ligation of Fc gamma RIII alpha (CD16) stimulates expression of many cytokinesvia Ca('2+) -depend mechanism [10]. Both ZAP70 and Sykphosphorylate Linker for activation of T cells ( LAT ) [7], [11]. LAT activates Phospholipases C gamma 1 and 2 ( PLC-gamma 1 and2 ), which control intracellular concentration of Ca('2+) [12],[13]. Ca('2+) activates Calmodulin 2 ( Calmodulin )/ Proteinphosphatase 3 ( Calcineurin ) signal. Activated Calcineurindephosphorylates Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2( NF-AT1(NFATC2) ). NF-AT1(NFATC2), in turn, migrates to the nucleus andactivates transcription of cytokines Tumor necrosis factor ( TNF-alpha ), Colonystimulating factor 2 ( GM-CSF ), Interleukin 2 ( IL-2 ), Interleukin 3 (IL-3 ), Interleukin 4 ( IL-4 ) [14], Fas ligand ( FasL )[15] and, possibly, Interferon gamma ( IFN-gamma ) [16].

These cytokines play various roles in immune response. FasL participates inlysis of target cells [17], [18], [19], [20], [21], [22].

The second mechanism leading to cytokines transcription in NK cells is by activationof v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-RAS ) via SHCtransforming protein 1 ( Shc )/ Growth factor receptor-bound protein 2 (Grb2 )/ Son of sevenless homologes ( SOS ) cascade [23], [24]. H-RAS activates v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1 )/ Mitogen-activated protein kinase kinases 1 and 2 ( MEK1(MAP2K1)and MEK2(MAP2K2) )/ Mitogen-activated protein kinases 3 and 1 ( ERK1 andERK2 ) cascade [25], [24], [26]. ERK1and ERK2 phosphorylate Jun oncogene ( c-Jun ) and V-fos FBJ murineosteosarcoma viral oncogene homolog ( c-Fos ), which form homo- and hetero-dimmerscomplex AP-1 and participate in activation of transcription TNF-alpha[27], IL-2 [14] and GM-CSF [14].

On the other hand, Fc gamma RIII alpha (CD16) ligation induces pathways leadingto exocytosis of secretory lysosomes [28]. PLC-gamma 2 probablyparticipates in the first pathway leading to cytoskeleton rearrangement [29].It catalyzes diacylglycerol ( DAG ) synthesis leading to activation of Proteinkinase C theta ( PKC-theta ) [30], [31]. PKC-thetaphosphorylates Wiskott-Aldrich syndrome protein interacting protein ( WaspIP )which leads to separation of WaspIP from Wiskott-Aldrich syndrome ( WASP ),activation of WASP and, eventually, rearrangement of Actin cytoskeletalthrough Apr2/3 complex. Actin cytoskeletal rearrangement may be alsorequired for cytolysis of target cell [32].

The second pathway leading to exocytosis starts from Syk and ZAP70,which phosphorylates Vav 1 guanine nucleotide exchange factor ( VAV-1 ) directly[33], [34]. Then VAV-1 participates in activation ofRas-related C3 botulinum toxin substrate 1 ( Rac1 ) [35], [34]. This pathway proceeds from Rac1 to formation of granules [35], [36]. In addition, VAV-1 may activate Cell division cycle 42( CDC42 ), which participates in activation of WASP [37],[32].

Another pathway which leads to secretion of granules includes Syk/ Cas-Br-Mecotropic retroviral transforming sequence ( c-Cbl )/ Phosphoinositide 3-kinase (PI3K ) cascade, which activates Pleckstrin homology, Sec7 and coiled-coil domains1 ( Cytohesin1 ). Grb2 probably helps to activate c-Cbl [38]. Cytohesin1 activates ADP-ribosylation factor 6 Arf6 [39], [40]. From Arf6, signal proceeds toPhosphatidylinositol-4-phosphate 5-kinase type I alpha ( PIP5K1A ) andPhospholipase D1 phosphatidylcholine-specific ( PLD1 ) directly and/or viaPIP5K1A. The products of reactions of both PIP5KA1 and PLD1participate in the vesicle secretion [41].

ERK2 also participates in degranulation via activation of Phospholipase A2group IIA ( PLA2 ) by phosphorylation [42], [43].

Inhibitory receptor Killer cell lectin-like receptor subfamily C, member 1 (NKG2A ) and Killer cell lectin-like receptor subfamily D, member 1 ( CD94 )deactivate stimulation from Fc gamma RIII alpha (CD16) after ligation ClassicalMHC class I molecules major histocompatibility complex, class I E ( HLA-E ) toNKG2A. It attracts Protein tyrosine phosphatase non-receptor type 6 (SHP-1 ), which dephosphorylates CD3 zeta, Syk and Shc [24].

Fc gamma RIII alpha (CD16) autoregulates activation of downstream signalstrough CD3 zeta/ Shc/ Inositol polyphosphate-5-phosphatase 145kDa (SHIP ) pathway. The hypothetical mechanism consists of SHIP participationin inhibition of Ca('2+) -depend pathway and signal from PI3K via decreasedamount IP3 [44] and PtdIns(3,4,5)P3 [45].