Here we have identified a surface protein, TIGIT, containing an immunoglobulin variable domain, a transmembrane domain and an immunoreceptor tyrosine-based inhibitory motif that was expressed on regulatory, memory and activated T cells. Poliovirus receptor, which is expressed on dendritic cells, bound TIGIT with high affinity. A TIGIT-Fc fusion protein inhibited T cell activation in vitro, and this was dependent on the presence of dendritic cells. The binding of poliovirus receptor to TIGIT on human dendritic cells enhanced the production of interleukin 10 and diminished the production of interleukin 12p40. Knockdown of TIGIT with small interfering RNA in human memory T cells did not affect T cell responses. TIGIT-Fc inhibited delayed-type hypersensitivity reactions in wild-type but not interleukin 10-deficient mice. Our data suggest that TIGIT exerts immunosuppressive effects by binding to poliovirus receptor and modulating cytokine production by dendritic cells.
"PVR encodes for CD155, a transmembrane glycoprotein that mediates NK cell adhesion and effector function (Sakisaka and Takai 2004). Multiple T cell and NK cell receptors (TIGIT, DNAM-1, CD96) interact with PVR and its related proteins and these interactions modulate T and NK cell activity (Bottino et al. 2003; Fuchs et al. 2004; Yu et al. 2009). In fact, PVR and related proteins interact with a wide variety of ligands and participate in multiple immunologic functions and serve as cellular receptors for poliovirus, rhinovirus, and reovirus (Xu and Jin 2010). "
[Show abstract][Hide abstract] ABSTRACT: Rubella virus causes a relatively benign disease in most cases, although infection during pregnancy can result in serious birth defects. An effective vaccine has been available since the early 1970s and outbreaks typically do not occur among highly vaccinated (≥2 doses) populations. Nevertheless, considerable inter-individual variation in immune response to rubella immunization does exist, with single-dose seroconversion rates ~95 %. Understanding the mechanisms behind this variability may provide important insights into rubella immunity. In the current study, we examined associations between single nucleotide polymorphisms (SNPs) in selected cytokine, cytokine receptor, and innate/antiviral genes and immune responses following rubella vaccination in order to understand genetic influences on vaccine response. Our approach consisted of a discovery cohort of 887 subjects aged 11-22 at the time of enrollment and a replication cohort of 542 older adolescents and young adults (age 18-40). Our data indicate that SNPs near the butyrophilin genes (BTN3A3/BTN2A1) and cytokine receptors (IL10RB/IFNAR1) are associated with variations in IFNγ secretion and that multiple SNPs in the PVR gene, as well as SNPs located in the ADAR gene, exhibit significant associations with rubella virus-specific IL-6 secretion. This information may be useful, not only in furthering our understanding immune responses to rubella vaccine, but also in identifying key pathways for targeted adjuvant use to boost immunity in those with weak or absent immunity following vaccination.
Human Genetics 08/2014; 133(11). DOI:10.1007/s00439-014-1471-z · 4.82 Impact Factor
"The TIGIT/CD226 pathway has been associated with several human autoimmune diseases  and studies in mice demonstrate that interference in this pathway may be an attractive approach to modulate autoimmune diseases. , ,  In the present study we determined the role of TIGIT in atherosclerosis. "
[Show abstract][Hide abstract] ABSTRACT: Co-stimulatory and co-inhibitory molecules are mainly expressed on T cells and antigen presenting cells and strongly orchestrate adaptive immune responses. Whereas co-stimulatory molecules enhance immune responses, signaling via co-inhibitory molecules dampens the immune system, thereby showing great therapeutic potential to prevent cardiovascular diseases. Signaling via co-inhibitory T cell immunoglobulin and ITIM domain (TIGIT) directly inhibits T cell activation and proliferation, and therefore represents a novel therapeutic candidate to specifically dampen pro-atherogenic T cell reactivity. In the present study, we used an agonistic anti-TIGIT antibody to determine the effect of excessive TIGIT-signaling on atherosclerosis.
TIGIT was upregulated on CD4(+) T cells isolated from mice fed a Western-type diet in comparison with mice fed a chow diet. Agonistic anti-TIGIT suppressed T cell activation and proliferation both in vitro and in vivo. However, agonistic anti-TIGIT treatment of LDLr(-/-) mice fed a Western-type diet for 4 or 8 weeks did not affect atherosclerotic lesion development in comparison with PBS and Armenian Hamster IgG treatment. Furthermore, elevated percentages of dendritic cells were observed in the blood and spleen of agonistic anti-TIGIT-treated mice. Additionally, these cells showed an increased activation status but decreased IL-10 production.
Despite the inhibition of splenic T cell responses, agonistic anti-TIGIT treatment does not affect initial atherosclerosis development, possibly due to increased activity of dendritic cells.
PLoS ONE 12/2013; 8(12):e83134. DOI:10.1371/journal.pone.0083134 · 3.23 Impact Factor
"Based on the critical role of DNAM-1 in NK cell biology, it is also important to discuss the role of two other receptors that share common ligands with DNAM-1: CD96 (Tactile) and TIGIT (WUCAM, VSTM3). TIGIT is an immune cell-specific immunoglobulin protein of the CD28 family discovered by Yu et al. 78 in 2009 consisting of one extracellular immunoglobulin domain, a type-1 transmembrane region and two ITIM motifs. In healthy humans, TIGIT is preferentially expressed by CD45RO þ memory T cells, CD4 þ FOXP3 þ regulatory T cells (T reg ) and NK cells. "
[Show abstract][Hide abstract] ABSTRACT: Natural killer (NK) cells represent key innate immune cells that restrain viral infection and malignant transformation and help mount an adaptive immune response. To perform such complicated tasks, NK cells express a wide set of inhibitory and activating receptors that alert them against cellular stress without damaging healthy cells. A new family of receptors that recognize nectin and nectin-like molecules has recently emerged as a critical regulator of NK cell functions. The most famous member of this family, DNAX accessory molecule (DNAM-1, CD226), is an adhesion molecule that control NK cell cytotoxicity and interferon-γ production against a wide range of cancer and infected cells. Its ligands CD112 and CD155 have been described in different pathological conditions, and recent evidence indicates that their expression is regulated by cellular stress. Additional receptors have been shown to bind DNAM-1 ligands and modulate NK cell functions bringing another level of complexity. These include CD96 (TACTILE) and TIGIT (WUCAM, VSTM3). Here, we review the role of DNAM-1, TIGIT and CD96 in NK cell biology summarizing the recent advances made on the role of these receptors in various pathologies, such as cancer, viral infections and autoimmunity.Immunology and Cell Biology advance online publication, 17 December 2013; doi:10.1038/icb.2013.95.
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