TIGIT

What is TIGIT protein?

Discovered in 2009, the T cell immunoreceptor with Ig and ITIM domains (TIGIT) has emerged as an essential player in the immunosuppression scene. This protein is a vital member of the immunoglobulin superfamily, known for their role in immunity, cell-cell recognition, and cell surface receptors.

Chronologically, Hafler's team initially discovered the TIGIT protein during research investigating the mechanisms regulating immune responses in multiple sclerosis. Through the genetic sequencing of T-cells, the team unveiled the existence of the TIGIT gene.

TIGIT gene locus is located on chromosome 3q13.31. This gene encodes a protein comprising two immunoglobulin (Ig) domains, a transmembrane domain, and an immunoreceptor tyrosine-based inhibitory motif (ITIM). The protein structure is distinct and systematic with an N-terminal IgV domain, playing a crucial role in binding to its ligands, followed by a C2-type Ig domain without a known function.

Functions of TIGIT Protein

Expressed primarily on immune cells, predominantly T cells, natural killer (NK) cells, and Regulatory T cells, TIGIT plays a cardinal role in the immune system's function. TIGIT works as a checkpoint inhibitor, meaning it can impede immune responses, allowing cancer cells to grow undeterred, hence its association with diseases such as cancer.

Prominently, TIGIT competes with another co-stimulatory receptor, CD226, for binding to the nectin and nectin-like families. TIGIT's affinity for these families is high, leading to the suppression of the immune response usually prompted by CD226 binding to the same ligands. When TIGIT binds to CD155 or CD112, an inhibitory signal is sent to the immune cells, suppressing the immune response.

TIGIT-Related Signal Pathway

The signaling pathway of TIGIT is vital to understanding its comprehensive function. Once bound to its ligands, TIGIT exhibits its ITIM and ITT-like motifs and recruits the protein tyrosine phosphatases SHP1 and SHP2. This initiation interferes with the downstream signaling pathways, ultimately leading to decreased immune cell activation and secretion of certain cytokines, dampening the immune response.

TIGIT-related Diseases

The in-depth study of TIGIT revealed its association with several diseases. Most notably, it's tied to malignancies like melanoma, colorectal cancer, breast cancer, and hematological cancers. The elevated expression of TIGIT has been recognized on tumor-infiltrating T cells and associated with a significantly worse prognosis across various cancers.

Also, TIGIT has been implicated in autoimmune and infectious diseases. For instance, TIGIT expression is found to be upregulated in CD4 + T cells in Multiple Sclerosis, Rheumatoid Arthritis, and Type 1 Diabetes patients. TIGIT's inhibitory role has raised the question about the protein's role in the evolution of chronic viral infections, considering its expression is upregulated on T cells during viral infections.

•  Cancer: Expression of TIGIT ligands by tumors inhibits anti-tumor T cells, promoting immune evasion. Blocking TIGIT can enhance immune-based cancer therapies.
•  Chronic infections: Persistent pathogens like HIV, HCV, HBV induce TIGIT expression, contributing to T cell exhaustion and dysfunctional immunity.
•  Autoimmunity: Upregulation of TIGIT helps prevent autoimmune pathology by maintaining tolerance of self-reactive T cells in tissues.
•  Transplant rejection: TIGIT signaling inhibition may improve transplant acceptance by regulating alloreactive T cell responses against donor antigens.
•  Cancer immunotherapy: Antibodies blocking TIGIT/CD155 interaction aim to reverse T cell exhaustion and boost anti-tumor immunity.
•  Transplantation: TIGIT inhibitors given with other immunosuppressants may help acceptance of transplanted organs by modulating allograft-reactive T cells.
•  Vaccine adjuvant: TIGIT blockade enhances T cell responses and memory induction, improving efficacy of vaccines for chronic infections.

Due to its function as an inhibitory immune checkpoint, the TIGIT protein has become an appealing target for immunotherapy, particularly in cancers. This approach aims to block TIGIT's inhibitory effects to allow an enhanced immune response against cancer cells. Numerous pharmaceutical companies are currently in a race to develop anti-TIGIT therapies, with several anti-TIGIT antibodies in clinical trials for various cancers.

Furthermore, TIGIT protein could have potential applications in treating autoimmune disorders. By harnessing the inhibitory properties of TIGIT, therapies could be developed to reduce the overactive immune responses seen in autoimmune diseases.

•  Cancer immunotherapy: Antibodies blocking TIGIT/CD155 interaction aim to reverse T cell exhaustion and boost anti-tumor immunity.
•  Transplantation: TIGIT inhibitors given with other immunosuppressants may help acceptance of transplanted organs by modulating allograft-reactive T cells.
•  Vaccine adjuvant: TIGIT blockade enhances T cell responses and memory induction, improving efficacy of vaccines for chronic infections.

TIGIT has several biochemical functions, for example, cell adhesion molecule binding,protein binding,protein homodimerization activity. Some of the functions are cooperated with other proteins, some of the functions could acted by TIGIT itself. We selected most functions TIGIT had, and list some proteins which have the same functions with TIGIT. You can find most of the proteins on our site.

TIGIT has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with TIGIT here. Most of them are supplied by our site. Hope this information will be useful for your research of TIGIT.

CD226;PVR;PVRL2;PVRL4;PVRL3