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) ) , . The preferred ligands for Fc gammaRIII alpha (CD16) on NK cells are Immunoglobulins gamma 1 and 3 ( IgG1 andIgG3 ) , . Fc gamma RIII alpha (CD16)covalently associates with the Membrane-bound signaling adaptor CD247 molecule ( CD3zeta ), which transduces signal to cytoplasm , . Uponligand binding and receptor activation, CD3 zeta is phosphorilated byLymphocyte-specific protein tyrosine kinase ( Lck ) and Zeta-chain associated protein kinase 70kDa ( ZAP70 ) , . Ligation of Fc gamma RIII alpha (CD16) stimulates expression of many cytokinesvia Ca('2+) -depend mechanism . Both ZAP70 and Sykphosphorylate Linker for activation of T cells ( LAT ) , . LAT activates Phospholipases C gamma 1 and 2 ( PLC-gamma 1 and2 ), which control intracellular concentration of Ca('2+) ,. 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 ) , Fas ligand ( FasL ) and, possibly, Interferon gamma ( IFN-gamma ) . These cytokines play various roles in immune response. FasL participates inlysis of target cells , , , , , . 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 , . 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 , , . 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, IL-2  and GM-CSF . On the other hand, Fc gamma RIII alpha (CD16) ligation induces pathways leadingto exocytosis of secretory lysosomes . PLC-gamma 2 probablyparticipates in the first pathway leading to cytoskeleton rearrangement .It catalyzes diacylglycerol ( DAG ) synthesis leading to activation of Proteinkinase C theta ( PKC-theta ) , . 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 . The second pathway leading to exocytosis starts from Syk and ZAP70,which phosphorylates Vav 1 guanine nucleotide exchange factor ( VAV-1 ) directly, . Then VAV-1 participates in activation ofRas-related C3 botulinum toxin substrate 1 ( Rac1 ) , . This pathway proceeds from Rac1 to formation of granules , . In addition, VAV-1 may activate Cell division cycle 42( CDC42 ), which participates in activation of WASP ,. 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 . Cytohesin1 activates ADP-ribosylation factor 6 Arf6 , . 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 . ERK2 also participates in degranulation via activation of Phospholipase A2group IIA ( PLA2 ) by phosphorylation , . 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 . 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  and PtdIns(3,4,5)P3 .