Immune response - Role of integrins in NK cells cytotoxicity

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Role of integrins in NK cells cytotoxicity

Natural killer (NK) cells are lymphocytes of innate immune system. They recognize and kill aberrant cells without immunization or pre-activation, by releasing cytotoxic granules and rapidly produce soluble factors - chemokines and cytokines. NK cells feature a variety of cell surface receptors, and their engagement determines whether NK cells will attack target cells [1], [2].

Integrin receptors are adhesion receptors involved in NK cells migration, adhesion of NK cell to target cell and the follow-up cytotoxicity. This map displays signaling of three adhesion receptors - alpha-L/beta-2 integrin, alpha-M/beta-2 integrin and alpha-4/beta-1 integrin.

The common ligand for alpha-L/beta-2integrin and alpha-M/beta-2integrin is Intercellular adhesion molecule 1 (ICAM1) [3], [4]. In addition, alpha-L/beta-2 integrin binds Intercellular adhesion molecule 2 (ICAM2) [5] and Intercellular adhesion molecule 3 (ICAM3) [6]. Fibronectin [7] and Vascular cell adhesion molecule 1 (VCAM1) [4], [8] are the ligands for alpha-4/beta-1 integrin cells.

Ligand-receptor binding leads to activation of PTK2B protein tyrosine kinase 2 beta (Pyk2(FAK2)) [4], [9], [10]. Activation of Pyk2(FAK2) from integrins is probably realized via Guanine nucleotide binding protein beta polypeptide 2-like 1 (RACK1)/ Protein kinase C, epsilon (PKC-epsilon) pathway [11].

Alpha-4/beta-1 integrin- and/or alpha-L/beta-2 integrin-activated Pyk2(FAK2) are associated with Vav 1 guanine nucleotide exchange factor (VAV-1), which undergoes tyrosine phosphorylation upon integrin triggering (e.g., via FYN oncogene related to SRC, FGR, YES (Fyn) [12], [13]). The phosphorylated VAV-1 activates ras-related C3 botulinum toxin substrate 1 (RAC1)/ p21 protein (Cdc42/Rac)-activated kinase 1 (PAK1) cascade. Signals from PAK1 lead to cytoskeleton rearrangement, formation of a stable lamellipodium and following transendothelial migration NK cells to target cells [4], [14].

Then a NK cell finds and binds to the surface of target cells.

Alpha-L/beta-2 integrin and alpha-4/beta-1 integrin participate in NK cells adhesion to targets via Paxillin and Pyk2(FAK2) [15]. The exact mechanism of adhesion is unknown [16], [17].

In addition, Alpha-L/beta-2 integrin and alpha-4/beta-1 integrin participate in cytotoxicity of NK cells [6], [18].

Ligand-receptor binding leads to activation Mitogen-activated protein kinases 3 and 1 (ERK1 and ERK2, accordingly), probably, via Pyk2(FAK2)/ Src homology 2 domain-containing transforming protein 1 (Shc)/ Growth factor receptor-bound protein 2 (GRB2) interactions. GRB2 activates positive regulator of Son of sevenless homolog (SOS), which results in activation of v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras)/ v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ Mitogen-activated protein kinase kinases 1 and 2 (MEK1(MAP2K1) MEK2(MAP2K2))/ Mitogen activated protein kinases 1-3 (ERK1/2) pathway [18].

Activation of ICAM-2 (and/or ICAM-3)/ Alpha-L/beta-2 integrin-dependent ERK1/2 leads to mobilization of lytic granules with perforin and granzyme B [6].

In addition, alpha-4/beta-1 integrin and alpha-L/beta-2 integrin may activate transcription of certain cytokines which participate in NK cell cytotoxicity [18], [19], [20].

Activation of Fibronectin/ alpha-4/beta-1 integrin-dependent ERK1/2 leads to stimulation of Interferon gamma (IFN-famma) transcription, probably, via v-fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos), Activating transcription factor 2 (ATF-2) or other [18]. Moreover, alpha-4/beta-1 integrin may activate Pyk2(FAK2)/ ras-related C3 botulinum toxin substrate 1 RAC1/ PAK1/ Mitogen-activated protein kinase kinase kinase 1 (MEKK1(MAP3K1))/ Mitogen-activated protein kinase kinase 3 (MEK3(MAP2K3))/ Mitogen-activated protein kinases 11-14 (p38MAPK) cascade. p38MAPK, in turn, increases transcription of Interleukin 8 (IL-8), possibly, via c-Fos [19].

Alpha-L/beta-2 integrin may activate transcription of FasL via an unknown pathway [20], probably via ERK1/2- and/or p38 MAPK.

Integrin action in NK cells is repressed by inhibitory receptors [20], [21]. Inhibitory receptors block signals from activating receptors with the aid of help attraction of phosphatase and following dephosphorylation of signaling proteins which proceed from activating receptors. Two phosphatases bind to ligand-bound inhibitory receptors Protein tyrosine phosphatases, non-receptor type 6 (SHP-1) and 11 (SHP-2) [22], [23].

During Alpha-L/beta-2 integrin-dependent activation of Fas ligand (FasL) transcription is inhibited by Killer cell lectin-like receptor subfamily C, member 1 (NKG2A)/ Killer cell lectin-like receptor subfamily D, member 1 (CD94) [20].

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. Chong AS, Boussy IA, Jiang XL, Lamas M, Graf LH Jr
    CD54/ICAM-1 is a costimulator of NK cell-mediated cytotoxicity. Cellular immunology 1994 Aug;157(1):92-105
  4. Gismondi A, Jacobelli J, Strippoli R, Mainiero F, Soriani A, Cifaldi L, Piccoli M, Frati L, Santoni A
    Proline-rich tyrosine kinase 2 and Rac activation by chemokine and integrin receptors controls NK cell transendothelial migration. Journal of immunology (Baltimore, Md. : 1950) 2003 Mar 15;170(6):3065-73
  5. Somersalo K, Carpen O, Saksela E, Gahmberg CG, Nortamo P, Timonen T
    Activation of natural killer cell migration by leukocyte integrin-binding peptide from intracellular adhesion molecule-2 (ICAM-2). The Journal of biological chemistry 1995 Apr 14;270(15):8629-36
  6. Perez OD, Mitchell D, Jager GC, Nolan GP
    LFA-1 signaling through p44/42 is coupled to perforin degranulation in CD56+CD8+ natural killer cells. Blood 2004 Aug 15;104(4):1083-93
  7. Wu C, Fields AJ, Kapteijn BA, McDonald JA
    The role of alpha 4 beta 1 integrin in cell motility and fibronectin matrix assembly. Journal of cell science 1995 Feb;108 ( Pt 2):821-9
  8. Rose DM, Liu S, Woodside DG, Han J, Schlaepfer DD, Ginsberg MH
    Paxillin binding to the alpha 4 integrin subunit stimulates LFA-1 (integrin alpha L beta 2)-dependent T cell migration by augmenting the activation of focal adhesion kinase/proline-rich tyrosine kinase-2. Journal of immunology (Baltimore, Md. : 1950) 2003 Jun 15;170(12):5912-8
  9. Gismondi A, Jacobelli J, Mainiero F, Paolini R, Piccoli M, Frati L, Santoni A
    Cutting edge: functional role for proline-rich tyrosine kinase 2 in NK cell-mediated natural cytotoxicity. Journal of immunology (Baltimore, Md. : 1950) 2000 Mar 1;164(5):2272-6
  10. Duong LT, Rodan GA
    PYK2 is an adhesion kinase in macrophages, localized in podosomes and activated by beta(2)-integrin ligation. Cell motility and the cytoskeleton 2000 Nov;47(3):174-88
  11. Besson A, Wilson TL, Yong VW
    The anchoring protein RACK1 links protein kinase Cepsilon to integrin beta chains. Requirements for adhesion and motility. The Journal of biological chemistry 2002 Jun 14;277(24):22073-84
  12. Rabinowich H, Manciulea M, Herberman RB, Whiteside TL
    Beta1 integrin-mediated activation of focal adhesion kinase and its association with Fyn and Zap-70 in human NK cells. Journal of immunology (Baltimore, Md. : 1950) 1996 Nov 1;157(9):3860-8
  13. Arias-Salgado EG, Lizano S, Shattil SJ, Ginsberg MH
    Specification of the direction of adhesive signaling by the integrin beta cytoplasmic domain. The Journal of biological chemistry 2005 Aug 19;280(33):29699-707
  14. Riteau B, Barber DF, Long EO
    Vav1 phosphorylation is induced by beta2 integrin engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization. The Journal of experimental medicine 2003 Aug 4;198(3):469-74
  15. Morris MA, Ley K
    Trafficking of natural killer cells. Current molecular medicine 2004 Jun;4(4):431-8
  16. Gismondi A, Bisogno L, Mainiero F, Palmieri G, Piccoli M, Frati L, Santoni A
    Proline-rich tyrosine kinase-2 activation by beta 1 integrin fibronectin receptor cross-linking and association with paxillin in human natural killer cells. Journal of immunology (Baltimore, Md. : 1950) 1997 Nov 15;159(10):4729-36
  17. Sancho D, Nieto M, Llano M, Rodriguez-Fernandez JL, Tejedor R, Avraham S, Caba?as C, Lopez-Botet M, Sanchez-Madrid F
    The tyrosine kinase PYK-2/RAFTK regulates natural killer (NK) cell cytotoxic response, and is translocated and activated upon specific target cell recognition and killing. The Journal of cell biology 2000 Jun 12;149(6):1249-62
  18. Mainiero F, Gismondi A, Soriani A, Cippitelli M, Palmieri G, Jacobelli J, Piccoli M, Frati L, Santoni A
    Integrin-mediated ras-extracellular regulated kinase (ERK) signaling regulates interferon gamma production in human natural killer cells. The Journal of experimental medicine 1998 Oct 5;188(7):1267-75
  19. Mainiero F, Soriani A, Strippoli R, Jacobelli J, Gismondi A, Piccoli M, Frati L, Santoni A
    RAC1/P38 MAPK signaling pathway controls beta1 integrin-induced interleukin-8 production in human natural killer cells. Immunity 2000 Jan;12(1):7-16
  20. Chua HL, Serov Y, Brahmi Z
    Regulation of FasL expression in natural killer cells. Human immunology 2004 Apr;65(4):317-27
  21. V?tvicka V, Hanikyrova M, V?tvickova J, Ross GD
    Regulation of CR3 (CD11b/CD18)-dependent natural killer (NK) cell cytotoxicity by tumour target cell MHC class I molecules. Clinical and experimental immunology 1999 Feb;115(2):229-35
  22. Yusa S, Campbell KS
    Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2) can play a direct role in the inhibitory function of killer cell Ig-like receptors in human NK cells. Journal of immunology (Baltimore, Md. : 1950) 2003 May 1;170(9):4539-47
  23. Moretta L, Bottino C, Pende D, Vitale M, Mingari MC, Moretta A
    Different checkpoints in human NK-cell activation. Trends in immunology 2004 Dec;25(12):670-6

  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. Chong AS, Boussy IA, Jiang XL, Lamas M, Graf LH Jr
    CD54/ICAM-1 is a costimulator of NK cell-mediated cytotoxicity. Cellular immunology 1994 Aug;157(1):92-105
  4. Gismondi A, Jacobelli J, Strippoli R, Mainiero F, Soriani A, Cifaldi L, Piccoli M, Frati L, Santoni A
    Proline-rich tyrosine kinase 2 and Rac activation by chemokine and integrin receptors controls NK cell transendothelial migration. Journal of immunology (Baltimore, Md. : 1950) 2003 Mar 15;170(6):3065-73
  5. Somersalo K, Carpen O, Saksela E, Gahmberg CG, Nortamo P, Timonen T
    Activation of natural killer cell migration by leukocyte integrin-binding peptide from intracellular adhesion molecule-2 (ICAM-2). The Journal of biological chemistry 1995 Apr 14;270(15):8629-36
  6. Perez OD, Mitchell D, Jager GC, Nolan GP
    LFA-1 signaling through p44/42 is coupled to perforin degranulation in CD56+CD8+ natural killer cells. Blood 2004 Aug 15;104(4):1083-93
  7. Wu C, Fields AJ, Kapteijn BA, McDonald JA
    The role of alpha 4 beta 1 integrin in cell motility and fibronectin matrix assembly. Journal of cell science 1995 Feb;108 ( Pt 2):821-9
  8. Rose DM, Liu S, Woodside DG, Han J, Schlaepfer DD, Ginsberg MH
    Paxillin binding to the alpha 4 integrin subunit stimulates LFA-1 (integrin alpha L beta 2)-dependent T cell migration by augmenting the activation of focal adhesion kinase/proline-rich tyrosine kinase-2. Journal of immunology (Baltimore, Md. : 1950) 2003 Jun 15;170(12):5912-8
  9. Gismondi A, Jacobelli J, Mainiero F, Paolini R, Piccoli M, Frati L, Santoni A
    Cutting edge: functional role for proline-rich tyrosine kinase 2 in NK cell-mediated natural cytotoxicity. Journal of immunology (Baltimore, Md. : 1950) 2000 Mar 1;164(5):2272-6
  10. Duong LT, Rodan GA
    PYK2 is an adhesion kinase in macrophages, localized in podosomes and activated by beta(2)-integrin ligation. Cell motility and the cytoskeleton 2000 Nov;47(3):174-88
  11. Besson A, Wilson TL, Yong VW
    The anchoring protein RACK1 links protein kinase Cepsilon to integrin beta chains. Requirements for adhesion and motility. The Journal of biological chemistry 2002 Jun 14;277(24):22073-84
  12. Rabinowich H, Manciulea M, Herberman RB, Whiteside TL
    Beta1 integrin-mediated activation of focal adhesion kinase and its association with Fyn and Zap-70 in human NK cells. Journal of immunology (Baltimore, Md. : 1950) 1996 Nov 1;157(9):3860-8
  13. Arias-Salgado EG, Lizano S, Shattil SJ, Ginsberg MH
    Specification of the direction of adhesive signaling by the integrin beta cytoplasmic domain. The Journal of biological chemistry 2005 Aug 19;280(33):29699-707
  14. Riteau B, Barber DF, Long EO
    Vav1 phosphorylation is induced by beta2 integrin engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization. The Journal of experimental medicine 2003 Aug 4;198(3):469-74
  15. Morris MA, Ley K
    Trafficking of natural killer cells. Current molecular medicine 2004 Jun;4(4):431-8
  16. Gismondi A, Bisogno L, Mainiero F, Palmieri G, Piccoli M, Frati L, Santoni A
    Proline-rich tyrosine kinase-2 activation by beta 1 integrin fibronectin receptor cross-linking and association with paxillin in human natural killer cells. Journal of immunology (Baltimore, Md. : 1950) 1997 Nov 15;159(10):4729-36
  17. Sancho D, Nieto M, Llano M, Rodriguez-Fernandez JL, Tejedor R, Avraham S, Caba?as C, Lopez-Botet M, Sanchez-Madrid F
    The tyrosine kinase PYK-2/RAFTK regulates natural killer (NK) cell cytotoxic response, and is translocated and activated upon specific target cell recognition and killing. The Journal of cell biology 2000 Jun 12;149(6):1249-62
  18. Mainiero F, Gismondi A, Soriani A, Cippitelli M, Palmieri G, Jacobelli J, Piccoli M, Frati L, Santoni A
    Integrin-mediated ras-extracellular regulated kinase (ERK) signaling regulates interferon gamma production in human natural killer cells. The Journal of experimental medicine 1998 Oct 5;188(7):1267-75
  19. Mainiero F, Soriani A, Strippoli R, Jacobelli J, Gismondi A, Piccoli M, Frati L, Santoni A
    RAC1/P38 MAPK signaling pathway controls beta1 integrin-induced interleukin-8 production in human natural killer cells. Immunity 2000 Jan;12(1):7-16
  20. Chua HL, Serov Y, Brahmi Z
    Regulation of FasL expression in natural killer cells. Human immunology 2004 Apr;65(4):317-27
  21. V?tvicka V, Hanikyrova M, V?tvickova J, Ross GD
    Regulation of CR3 (CD11b/CD18)-dependent natural killer (NK) cell cytotoxicity by tumour target cell MHC class I molecules. Clinical and experimental immunology 1999 Feb;115(2):229-35
  22. Yusa S, Campbell KS
    Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2) can play a direct role in the inhibitory function of killer cell Ig-like receptors in human NK cells. Journal of immunology (Baltimore, Md. : 1950) 2003 May 1;170(9):4539-47
  23. Moretta L, Bottino C, Pende D, Vitale M, Mingari MC, Moretta A
    Different checkpoints in human NK-cell activation. Trends in immunology 2004 Dec;25(12):670-6

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