TEK, or TIE-2, is an endothelial cell-specific receptor tyrosine kinase (RTK) that is known as a functioning molecule of vascular endothelial cells. TEK comprises a subfamily of RTK with TIE, and these two receptors play critical roles in vascular maturation, maintenance of integrity and remodeling. Targeted mutagenesis of both Tek and its agonistic ligand, Angiopoietin-1, result in embryonic lethality, demonstrating that the signal transduction pathways mediated by this receptor are crucial for normal embryonic development. TEK signaling is indispensable for the development of the embryonic vasculature and suggests that TEK signaling may also be required for the development of the tumor vasculature.
TIGIT, also known as V-set and transmembrane domain-containing protein 3 (VSTM3) or V-set and immunoglobulin domain-containing protein 9 (VSIG9) is a new surface protein containing an immunoglobulin variable domain, a transmembrane domain and an immunoreceptor tyrosine-based inhibitory motif (ITIM). TIGIT is expressed on regulatory, memory, activated T cells and NK cells. It binds PVR with high affinity, and PVRL2 with lower affinity, but not PVRL3. Knockdown of TIGIT with siRNA in human memory T cells did not affect T cell responses, however, TIGIT inhibits NK cytotoxicity directly through its ITIM. TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. The binding of PVR to TIGIT on human dendritic cells enhanced the production of IL-10 and diminished the production of IL-12p40. In addition, TIGIT counter inhibits the NK-mediated killing of tumor cells and protects normal cells from NK-mediated cytotoxicity thus providing an "alternative self" mechanism for MHC class I inhibition.
T cell immunoreceptor with Ig and ITIM domains (TIGIT), also called WUCAM, VSIG9 and Vstm3, is a member of the CD28 family within the Ig superfamily of proteins. TIGIT contains an immunoglobulin variable domain, a transmembrane domain and an immunoreceptor tyrosine-based inhibitory motif (ITIM), and is expressed on regulatory, memory, activated T cells and NK cells. TIGIT binds to CD155(PVR) that appear on dendritic cells (DC), macrophages and endothelium with high affinity, and CD112(PVRL2) with lower affinity, but not CD113 (PVRL3). TIGIT-Fc fusion protein could interact with PVR on DC and enhance the secretion of IL-10, but inhibit the macrophage activation. Mice lacking TIGIT show increased T cell responses and susceptibility to autoimmune challenges, while knockdown of TIGIT with siRNA in human memory T cells did not affect T cell responses.
HAV cellular receptor 1 (HAVCR1), also known as Kidney injury molecule 1 (KIM-1) and T cell immunoglobulinmucin 1 (TIM-1), is a type â… integral membrane glycoprotein. KIM-1 protein is widely expressed with highest levels in kidney and testis. It has been shown to play a major role as a human susceptibility gene for asthma, allergy and autoimmunity. IgA1lambda is a specific ligand of KIM-1 protein and that their association has a synergistic effect in virus-receptor interactions. KIM-1 involves in the pathogenesis of acute kidney injury. It had been confirmed that KIM-1 is a human urinary renal dysfunction biomarker. Moreover, KIM-1 protein is a novel regulatory molecule of flow-induced calcium signaling.
TIM-1/KIM-1/HAVCR belongs to the immunoglobulin superfamily that cosisits 305 amino acid (aa). It is expressed by stimulated T-cells. TIM-1/KIM-1/HAVCR may play a role in T-helper cell development and the regulation of asthma and allergic diseases. Receptor for TIMD4. And may have a role in kidney injury and repair. Belongs to the T-cell and airway phenotype regulator (Tapr) locus, a single chromosomal region that confers reduced T-helper type 2 responsiveness and protects against airway hyperactivity (AHR), the hallmark of human asthma.
Hepatitis A virus cellular receptor 2 (HAVCR2), formerly known as T cell immunoglobulin and mucin domain-3 (TIM-3), is a transmembrane glycoprotein expressed on the surface of terminally differentiated Th1 cells but not on Th2 cells. It was the first surface molecule that specifically identifies Th1 cells in both mice and human. Recently, identification of Galectin-9 as a ligand for TIM-3 has established the TIM-3-Galectin-9 pathway as an important regulator of Th1 immunity and tolerance induction. Engagement of Tim-3 by its ligand galectin-9 negatively regulates IFN-gamma secretion and influences the ability to induce T cell tolerance in both mice and man. It suggests a novel paradigm in which dysregulation of the TIM-3-galectin-9 pathway could underlie chronic autoimmune disease states, such as multiple sclerosis. Recent work has explored the role of TIM-3 in systemic lupus erythematosus (SLE), and their results indicate that TIM-3 may represent a novel target for the treatment of SLE. Numerous studies have demonstrated that Tim-3 influences autoimmune diseases, including diabetes and multiple sclerosis, and its role in other inflammatory diseases including allergies and cancer is beginning to become clear. In tumor rejection model, soluble form of Tim-3 (sTim-3) significantly impaired T cell antitumor immunity, evidenced by decreased antitumor CTL activity and reduced amount of tumor-infiltrating lymphocytes in tumor. sTim-3 as an immunoregulatory molecule that may be involved in the negative regulation of T cell-mediated immune response.
T cell immunoglobulin and mucin domain-3 (TIM3), also called hepatitis A virus cellular receptor 2 (HAVCR2), is a transmembrane glycoprotein of the TIM family of immune regulating molecules and plays an important role in the Th1-mediated immune response. TIM3 is expressed on the Th1 cells, CD8 T-cells, monocytes, and dendritic cells, but not on Th2 cells. TIM3 expressed by monocytes and dendritic cells facilitates phagocytosis of apoptotic cells and up-regulates cross-presentation of apoptotic cell-associated antigens through interaction with phosphatidylserine. Engagement of TIM3 by its ligand galectin-9 induces a range of immunosuppressive functions which enhance immune tolerance and inhibit anti-tumor immunity. Stimulation of TIM3 with an agonistic antibody promotes inflammation through the activation of innate immune cells. TIM3 is also regarded as a potential target molecule for immunotherapy. TIM3 and programmed cell death 1 (PD-1) as two important coinhibitory regulators of T cell responses, have been implicated with the T-cell dysfunction or exhaustion associated with chronic HBV infection including HBV-related HCC.
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