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TIGIT Inhibits NK Cell-Mediated Killing


TIGIT Inhibits NK Cell-Mediated Killing

NK Cell

Natural killer (NK) cells are a type of lymphocyte critical to the innate immunity. The critical role of NK cells involves rapid defense against pathogen infections, tumor cells and damaged cells. Unlike adaptive immune cells, NK cell-mediated killing do not require prior sensitization or antigens presented on targets. Their functions are accomplished through direct cytolysis, the release of cytokines and chemokines including interferon-γ (IFN-γ), tumor-necrosis factor-α (TNF-α), granulocyte-macrophage colony-stimulating factor (GM‑CSF), interleukin‑6 (IL‑6), CC‑chemokine ligand 3 (CCL3), CCL4 and CCL5.

The functions of NK cells are regulated by a wide range of activating receptors and inhibitory receptors, classified on the basis of the signals they transmit. The activating receptors, such as natural cytotoxicity receptors (NCRs), NKG2D or CD226, stimulates NK cell–mediated killing. In contrast, inhibitory receptors inhibits NK cell functions. Examples of inhibitory NK cell receptors include the KIR (killer cell immunoglobulin-like receptors) and LIR (leukocyte immunoglobulin-like receptors) in humans, the Ly49 family in mice, and heterodimers of the C-type lectin CD94 and NKG2 in both species. Those inhibitory receptors mainly recognize MHC-I molecules. T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) is a novel NK inhibitory receptors that bind nectin and nectin-like proteins instead of MHC-I molecules.

TIGIT

TIGIT, also known as VSIG9; VSTM3; WUCAM, is a member of inhibitory immune checkpoints. It is expressed mainly on the surface of T cells and NK cells and is composed of three domains: 1) an extracellular immunoglobulin variable (IgV) domain which is responsible for binding PVR, NECTIN2 and NECTIN3, 2) a transmembrane domain, and 3) an intracellular domain which includes the immunoreceptor tail tyrosine (ITT)-like and ITIM motifs. Physical ligands of TIGIT include PVR (PVS; HVED; CD155; NECL5; TAGE4; Necl-5) with higher affinity, NECTIN2 (HVEB; PRR2; CD112; PVRL2; PVRR2) and NECTIN3 (PPR3; PRR3; CD113; PVRL3; PVRR3; CDW113; NECTIN-3) with lower affinity.

Several published data support the suppression role of TIGIT on NK cells in vitro. For example, the killing of TIGIT transfected NK cells (YTS-TIGIT) was strongly inhibited compared with non-transfected NK cells (YTS), while the increased killing was observed after blockage of TIGIT using antibody.

TIGIT

The inhibitory mechanism has been elucidated which in brief is that TIGIT/PVR interaction leads to phosphorylation of TIGIT’s intracellular domain and further triggers intracellular signaling cascades to limit NK cell functions.

Recently, NK cells are an attractive cell population for cancer immunotherapy because their killing is MHC-independent thus they can kill cancer cells escaped from T cell-mediated immune response. TIGIT as an attractive immunomodulator protein, can regulates both NK and T cells. Thus screening of effective inhibitors of TIGIT should provide promising approaches for cancer treatment.

Our Capability

Creative Biogene offers complete products and services to assist scientists in studies related to TIGIT target.

Stable cell lines Human TIGIT Stable Cell Line-CHO
Mouse Tigit Stable Cell Line-CHO
Human CD226 Stable Cell Line-HEK293T
TNFα-Luc Reporter Cell Line-HEK293
IL6-Luc Reporter Cell Line-NIH3T3
Panoply™ Human CSF2 Over-expressing Stable Cell Line
Panoply™ Human CCL3 Over-expressing Stable Cell Line
Panoply™ Human CCL4 Over-expressing Stable Cell Line
Panoply™ Human CCL5 Over-expressing Stable Cell Line
Panoply™ Human PVR Over-expressing Stable Cell Line
Virus particles Human TIGIT lentiviral particles
Mouse Tigit lentiviral particles
Human TIGIT adenoviral particles
Human CD226 lentiviral particles
Mouse Cd226 lentiviral particles
Human CD226 adenoviral particles
Human IL6 (NM_000600) lentivirus particles
Human CSF2 adenoviral particles
Human CCL3 adenoviral particles
Human CCL3 (NM_002983) lentivirus particles
Human CCL4 adenoviral particles
Human CCL4 (NM_002984) lentivirus particles
Human CCL5 adenoviral particles
Human CCL5 (NM_002985) lentivirus particles
Human PVR lentiviral particles
Mouse Pvr lentiviral particles
Human PVR adenoviral particles
cDNAs Human TIGIT ORF clone (NM_173799.3)
Mouse TIGIT ORF clone(NM_001146325.1)
Human CD226 ORF clone (NM_006566.1)
Mouse CD226 ORF clone(NM_178687.2)
Mouse TNFα ORF clone(NM_013693.2)
Human IL6 ORF clone (NM_000600.2)
Mouse IL6 ORF clone(NM_031168.1)
Mouse CSF2 ORF clone(NM_009969.4)
Human CCL3 ORF clone(NM_002983.2)
Mouse Ccl3 ORF Clone(NM_011337.2)
Human CCL4 ORF clone(NM_002984.2)
Mouse CCL4 ORF clone(NM_013652.2)
Human CCL5 ORF clone(NM_002985.2)
Mouse CCL5 ORF clone(NM_013653.3)
Human PVR ORF clone (NM_001135769.1)
Mouse PVR ORF clone(NM_027514.2)

References:

  1. Martinet L, Smyth MJ. Balancing natural killer cell activation through paired receptors. Nature Reviews Immunology. 2015; 2: 243-254.
  2. Stanietsky N, Simic H, et al. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc. Natl Acad. Sci. USA. 2009; 42: 17858-17863.
  3. Wang F, Hou H, et al. TIGIT expression levels on human NK cells correlate with functional heterogeneity among healthy individuals. Eur J Immunol. 2015; 10:2886-2897.
  4. He Y, Peng H, et al. Contribution of inhibitory receptor TIGIT to NK cell education. J Autoimmun. 2017; 81:1-12.

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