Immune response - Role of integrins in NK cells cytotoxicity

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].

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