Immune response - CD16 signaling in NK cells

CD16 signaling in NK cells

Natural killer (NK) cells mediate antibody-depend cellular cytotoxicity through the Fc fragment of IgG, low affinity IIIa and receptor (CD16a) (Fc gamma RIII alpha (CD16)) [1], [2]. The preferred ligands for Fc gamma RIII alpha (CD16) on NK cells are Immunoglobulins gamma 1 and 3 (IgG1 and IgG3) [3], [4]. Fc gamma RIII alpha (CD16) covalently associates with the Membrane-bound signaling adaptor CD247 molecule (CD3 zeta), which transduces signal to cytoplasm [5], [6]. Upon ligand binding and receptor activation, CD3 zeta is phosphorilated by Lymphocyte-specific protein tyrosine kinase (Lck) [7], followed by recruitment of SYK family kinases - Spleen tyrosine kinase (Syk) [8] and Zeta-chain associated protein kinase 70kDa (ZAP70) [9], [10].

Ligation of Fc gamma RIII alpha (CD16) stimulates expression of many cytokines via Ca('2+) -depend mechanism [11]. Both ZAP70 and Syk phosphorylate Linker for activation of T cells (LAT) [8], [12]. LAT activates Phospholipases C gamma 1 and 2 (PLC-gamma 1 and 2), which control intracellular concentration of Ca('2+) [13], [14]. Ca('2+) activates Calmodulin 2 (Calmodulin)/ Protein phosphatase 3 (Calcineurin) signal. Activated Calcineurin dephosphorylates Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2 (NF-AT1(NFATC2)). NF-AT1(NFATC2), in turn, migrates to the nucleus and activates transcription of cytokines Tumor necrosis factor (TNF-alpha), Colony stimulating factor 2 (GM-CSF), Interleukin 2 (IL-2), Interleukin 3 (IL-3), Interleukin 4 (IL-4) [15], Fas ligand (FasL) [16] and, possibly, Interferon gamma (IFN-gamma) [17].

These cytokines play various roles in immune response. FasL participates in lysis of target cells [18], [19], [20], [21], [22], [23].

The second mechanism leading to cytokines transcription in NK cells is by activation of v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-RAS) via SHC transforming protein 1 (Shc)/ Growth factor receptor-bound protein 2 (Grb2)/ Son of sevenless homologes (SOS) cascade [24], [25]. 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 and ERK2) cascade [25], [26], [27]. ERK1 and ERK2 phosphorylate Jun oncogene (c-Jun) and V-fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos), which form homo- and hetero-dimmers complex AP-1 and participate in activation of transcription TNF-alpha [28], IL-2 [15] and GM-CSF [15].

On the other hand, Fc gamma RIII alpha (CD16) ligation induces pathways leading to exocytosis of secretory lysosomes [29]. PLC-gamma 2 probably participates in the first pathway leading to cytoskeleton rearrangement [30]. It catalyzes diacylglycerol (DAG) synthesis leading to activation of Protein kinase C theta (PKC-theta) [31], [32]. PKC-theta phosphorylates 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 cytoskeletal through Apr2/3 complex. Actin cytoskeletal rearrangement may be also required for cytolysis of target cell [33].

The second pathway leading to exocytosis starts from Syk and ZAP70, which phosphorylates Vav 1 guanine nucleotide exchange factor (VAV-1) directly [34], [35]. Then VAV-1 participates in activation of Ras-related C3 botulinum toxin substrate 1 (Rac1) [35], [36]. This pathway proceeds from Rac1 to formation of granules [36], [37]. In addition, VAV-1 may activate Cell division cycle 42 (CDC42), which participates in activation of WASP [33], [38].

Another pathway which leads to secretion of granules includes Syk/ Cas-Br-M ecotropic retroviral transforming sequence (c-Cbl)/ Phosphoinositide 3-kinase (PI3K) cascade, which activates Pleckstrin homology, Sec7 and coiled-coil domains 1 (Cytohesin1). Grb2 probably helps to activate c-Cbl [39]. Cytohesin1 activates ADP-ribosylation factor 6 Arf6 [40], [41]. From Arf6, signal proceeds to Phosphatidylinositol-4-phosphate 5-kinase type I alpha (PIP5K1A) and Phospholipase D1 phosphatidylcholine-specific (PLD1) directly and/or via PIP5K1A. The products of reactions of both PIP5KA1 and PLD1 participate in the vesicle secretion [42].

ERK2 also participates in degranulation via activation of Phospholipase A2 group IIA (PLA2) by phosphorylation [43], [44].

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 Classical MHC class I molecules major histocompatibility complex, class I E (HLA-E) to NKG2A. It attracts Protein tyrosine phosphatase non-receptor type 6 (SHP-1), which dephosphorylates CD3 zeta, Syk and Shc [25].

Fc gamma RIII alpha (CD16) autoregulates activation of downstream signals trough CD3 zeta / Shc / Inositol polyphosphate-5-phosphatase 145kDa (SHIP) pathway. The hypothetical mechanism consists of SHIP participation in inhibition of Ca('2+) -depend pathway and signal from PI3K via decreased amount IP3 [45] and PtdIns(3,4,5)P3 [46].

References:

1. Colucci F, Caligiuri MA, Di Santo JP
   What does it take to make a natural killer? Nature reviews. Immunology 2003 May;3(5):413-25
2. Farag SS, Caligiuri MA
   Human natural killer cell development and biology. Blood reviews 2006 May;20(3):123-37
3. de Haas M, Koene HR, Kleijer M, de Vries E, Simsek S, van Tol MJ, Roos D, von dem Borne AE
   A triallelic Fc gamma receptor type IIIA polymorphism influences the binding of human IgG by NK cell Fc gamma RIIIa. Journal of immunology (Baltimore, Md. : 1950) 1996 Apr 15;156(8):2948-55
4. Takai T
   Roles of Fc receptors in autoimmunity. Nature reviews. Immunology 2002 Aug;2(8):580-92
5. Galandrini R, Palmieri G, Paolini R, Piccoli M, Frati L, Santoni A
   Selective binding of shc-SH2 domain to tyrosine-phosphorylated zeta but not gamma-chain upon CD16 ligation on human NK cells. Journal of immunology (Baltimore, Md. : 1950) 1997 Oct 15;159(8):3767-73
6. Baniyash M
   TCR zeta-chain downregulation: curtailing an excessive inflammatory immune response. Nature reviews. Immunology 2004 Sep;4(9):675-87
7. Salcedo TW, Kurosaki T, Kanakaraj P, Ravetch JV, Perussia B
   Physical and functional association of p56lck with Fc gamma RIIIA (CD16) in natural killer cells. The Journal of experimental medicine 1993 May 1;177(5):1475-80
8. St?hls A, Liwszyc GE, Couture C, Mustelin T, Andersson LC
   Triggering of human natural killer cells through CD16 induces tyrosine phosphorylation of the p72syk kinase. European journal of immunology 1994 Oct;24(10):2491-6
9. Vivier E, da Silva AJ, Ackerly M, Levine H, Rudd CE, Anderson P
   Association of a 70-kDa tyrosine phosphoprotein with the CD16: zeta: gamma complex expressed in human natural killer cells. European journal of immunology 1993 Aug;23(8):1872-6
10. Maghazachi AA
    Insights into seven and single transmembrane-spanning domain receptors and their signaling pathways in human natural killer cells. Pharmacological reviews 2005 Sep;57(3):339-57
11. Cassatella MA, Anegon I, Cuturi MC, Griskey P, Trinchieri G, Perussia B
    Fc gamma R(CD16) interaction with ligand induces Ca2+ mobilization and phosphoinositide turnover in human natural killer cells. Role of Ca2+ in Fc gamma R(CD16)-induced transcription and expression of lymphokine genes. The Journal of experimental medicine 1989 Feb 1;169(2):549-67
12. Jevremovic D, Billadeau DD, Schoon RA, Dick CJ, Irvin BJ, Zhang W, Samelson LE, Abraham RT, Leibson PJ
    Cutting edge: a role for the adaptor protein LAT in human NK cell-mediated cytotoxicity. Journal of immunology (Baltimore, Md. : 1950) 1999 Mar 1;162(5):2453-6
13. Azzoni L, Kamoun M, Salcedo TW, Kanakaraj P, Perussia B
    Stimulation of Fc gamma RIIIA results in phospholipase C-gamma 1 tyrosine phosphorylation and p56lck activation. The Journal of experimental medicine 1992 Dec 1;176(6):1745-50
14. Ting AT, Karnitz LM, Schoon RA, Abraham RT, Leibson PJ
    Fc gamma receptor activation induces the tyrosine phosphorylation of both phospholipase C (PLC)-gamma 1 and PLC-gamma 2 in natural killer cells. The Journal of experimental medicine 1992 Dec 1;176(6):1751-5
15. Aramburu J, Azzoni L, Rao A, Perussia B
    Activation and expression of the nuclear factors of activated T cells, NFATp and NFATc, in human natural killer cells: regulation upon CD16 ligand binding. The Journal of experimental medicine 1995 Sep 1;182(3):801-10
16. Furuke K, Shiraishi M, Mostowski HS, Bloom ET
    Fas ligand induction in human NK cells is regulated by redox through a calcineurin-nuclear factors of activated T cell-dependent pathway. Journal of immunology (Baltimore, Md. : 1950) 1999 Feb 15;162(4):1988-93
17. Sica A, Dorman L, Viggiano V, Cippitelli M, Ghosh P, Rice N, Young HA
    Interaction of NF-kappaB and NFAT with the interferon-gamma promoter. The Journal of biological chemistry 1997 Nov 28;272(48):30412-20
18. Bossi G, Griffiths GM
    Degranulation plays an essential part in regulating cell surface expression of Fas ligand in T cells and natural killer cells. Nature medicine 1999 Jan;5(1):90-6
19. Malmgaard L
    Induction and regulation of IFNs during viral infections. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 2004 Aug;24(8):439-54
20. Marcenaro E, Della Chiesa M, Bellora F, Parolini S, Millo R, Moretta L, Moretta A
    IL-12 or IL-4 prime human NK cells to mediate functionally divergent interactions with dendritic cells or tumors. Journal of immunology (Baltimore, Md. : 1950) 2005 Apr 1;174(7):3992-8
21. Ortaldo JR, Winkler-Pickett RT, Bere EW Jr, Watanabe M, Murphy WJ, Wiltrout RH
    In vivo hydrodynamic delivery of cDNA encoding IL-2: rapid, sustained redistribution, activation of mouse NK cells, and therapeutic potential in the absence of NKT cells. Journal of immunology (Baltimore, Md. : 1950) 2005 Jul 15;175(2):693-9
22. Fleetwood AJ, Cook AD, Hamilton JA
    Functions of granulocyte-macrophage colony-stimulating factor. Critical reviews in immunology 2005;25(5):405-28
23. Mukhopadhyay S, Hoidal JR, Mukherjee TK
    Role of TNFalpha in pulmonary pathophysiology. Respiratory research 2006 Oct 11;7:125
24. Galandrini R, Palmieri G, Piccoli M, Frati L, Santoni A
    CD16-mediated p21ras activation is associated with Shc and p36 tyrosine phosphorylation and their binding with Grb2 in human natural killer cells. The Journal of experimental medicine 1996 Jan 1;183(1):179-86
25. Palmieri G, Tullio V, Zingoni A, Piccoli M, Frati L, Lopez-Botet M, Santoni A
    CD94/NKG2-A inhibitory complex blocks CD16-triggered Syk and extracellular regulated kinase activation, leading to cytotoxic function of human NK cells. Journal of immunology (Baltimore, Md. : 1950) 1999 Jun 15;162(12):7181-8
26. Trotta R, Puorro KA, Paroli M, Azzoni L, Abebe B, Eisenlohr LC, Perussia B
    Dependence of both spontaneous and antibody-dependent, granule exocytosis-mediated NK cell cytotoxicity on extracellular signal-regulated kinases. Journal of immunology (Baltimore, Md. : 1950) 1998 Dec 15;161(12):6648-56
27. Epling-Burnette PK, Bai F, Wei S, Chaurasia P, Painter JS, Olashaw N, Hamilton A, Sebti S, Djeu JY, Loughran TP
    ERK couples chronic survival of NK cells to constitutively activated Ras in lymphoproliferative disease of granular lymphocytes (LDGL). Oncogene 2004 Dec 9;23(57):9220-9
28. Trotta R, Kanakaraj P, Perussia B
    Fc gamma R-dependent mitogen-activated protein kinase activation in leukocytes: a common signal transduction event necessary for expression of TNF-alpha and early activation genes. The Journal of experimental medicine 1996 Sep 1;184(3):1027-35
29. Bryceson YT, March ME, Ljunggren HG, Long EO
    Activation, coactivation, and costimulation of resting human natural killer cells. Immunological reviews 2006 Dec;214:73-91
30. Caraux A, Kim N, Bell SE, Zompi S, Ranson T, Lesjean-Pottier S, Garcia-Ojeda ME, Turner M, Colucci F
    Phospholipase C-gamma2 is essential for NK cell cytotoxicity and innate immunity to malignant and virally infected cells. Blood 2006 Feb 1;107(3):994-1002
31. Borrego F, Lopez-Beltran A, Pe?a J, Solana R
    Downregulation of Fc gamma receptor IIIA alpha (CD16-II) on natural killer cells induced by anti-CD16 mAb is independent of protein tyrosine kinases and protein kinase C. Cellular immunology 1994 Oct 1;158(1):208-17
32. Sasahara Y, Rachid R, Byrne MJ, de la Fuente MA, Abraham RT, Ramesh N, Geha RS
    Mechanism of recruitment of WASP to the immunological synapse and of its activation following TCR ligation. Molecular cell 2002 Dec;10(6):1269-81
33. Krzewski K, Chen X, Orange JS, Strominger JL
    Formation of a WIP-, WASp-, actin-, and myosin IIA-containing multiprotein complex in activated NK cells and its alteration by KIR inhibitory signaling. The Journal of cell biology 2006 Apr 10;173(1):121-32
34. Xu X, Chong AS
    Vav in natural killer cells is tyrosine phosphorylated upon cross-linking of Fc gamma RIIIA and is constitutively associated with a serine/threonine kinase. The Biochemical journal 1996 Sep 1;318 ( Pt 2):527-32
35. Galandrini R, Palmieri G, Piccoli M, Frati L, Santoni A
    Role for the Rac1 exchange factor Vav in the signaling pathways leading to NK cell cytotoxicity. Journal of immunology (Baltimore, Md. : 1950) 1999 Mar 15;162(6):3148-52
36. Billadeau DD, Brumbaugh KM, Dick CJ, Schoon RA, Bustelo XR, Leibson PJ
    The Vav-Rac1 pathway in cytotoxic lymphocytes regulates the generation of cell-mediated killing. The Journal of experimental medicine 1998 Aug 3;188(3):549-59
37. Bryceson YT, March ME, Barber DF, Ljunggren HG, Long EO
    Cytolytic granule polarization and degranulation controlled by different receptors in resting NK cells. The Journal of experimental medicine 2005 Oct 3;202(7):1001-12
38. Gismondi A, Cifaldi L, Mazza C, Giliani S, Parolini S, Morrone S, Jacobelli J, Bandiera E, Notarangelo L, Santoni A
    Impaired natural and CD16-mediated NK cell cytotoxicity in patients with WAS and XLT: ability of IL-2 to correct NK cell functional defect. Blood 2004 Jul 15;104(2):436-43
39. Cerboni C, Gismondi A, Palmieri G, Piccoli M, Frati L, Santoni A
    CD16-mediated activation of phosphatidylinositol-3 kinase (PI-3K) in human NK cells involves tyrosine phosphorylation of Cbl and its association with Grb2, Shc, pp36 and p85 PI-3K subunit. European journal of immunology 1998 Mar;28(3):1005-15
40. Kanakaraj P, Duckworth B, Azzoni L, Kamoun M, Cantley LC, Perussia B
    Phosphatidylinositol-3 kinase activation induced upon Fc gamma RIIIA-ligand interaction. The Journal of experimental medicine 1994 Feb 1;179(2):551-8
41. Ogasawara M, Kim SC, Adamik R, Togawa A, Ferrans VJ, Takeda K, Kirby M, Moss J, Vaughan M
    Similarities in function and gene structure of cytohesin-4 and cytohesin-1, guanine nucleotide-exchange proteins for ADP-ribosylation factors. The Journal of biological chemistry 2000 Feb 4;275(5):3221-30
42. Galandrini R, Micucci F, Tassi I, Cifone MG, Cinque B, Piccoli M, Frati L, Santoni A
    Arf6: a new player in FcgammaRIIIA lymphocyte-mediated cytotoxicity. Blood 2005 Jul 15;106(2):577-83
43. Milella M, Gismondi A, Roncaioli P, Bisogno L, Palmieri G, Frati L, Cifone MG, Santoni A
    CD16 cross-linking induces both secretory and extracellular signal-regulated kinase (ERK)-dependent cytosolic phospholipase A2 (PLA2) activity in human natural killer cells: involvement of ERK, but not PLA2, in CD16-triggered granule exocytosis. Journal of immunology (Baltimore, Md. : 1950) 1997 Apr 1;158(7):3148-54
44. Milella M, Gismondi A, Roncaioli P, Palmieri G, Morrone S, Piccoli M, Frati L, Cifone MG, Santoni A
    Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells: role of phospholipase D in CD16-triggered degranulation. Journal of immunology (Baltimore, Md. : 1950) 1999 Feb 15;162(4):2064-72
45. Galandrini R, Tassi I, Morrone S, Lanfrancone L, Pelicci P, Piccoli M, Frati L, Santoni A
    The adaptor protein shc is involved in the negative regulation of NK cell-mediated cytotoxicity. European journal of immunology 2001 Jul;31(7):2016-25
46. Galandrini R, Tassi I, Mattia G, Lenti L, Piccoli M, Frati L, Santoni A
    SH2-containing inositol phosphatase (SHIP-1) transiently translocates to raft domains and modulates CD16-mediated cytotoxicity in human NK cells. Blood 2002 Dec 15;100(13):4581-9