Cutting Edge: TIGIT Has T Cell-Intrinsic Inhibitory Functions

Joller, Nicole; Hafler, Jason P.; Brynedal, Boel; Kassam, Nasim; Spoerl, Silvia; Levin, Steven D.; Sharpe, Arlene H.; Kuchroo, Vijay K.

doi:10.4049/jimmunol.1003081

Cited by 463 publications

(483 citation statements)

References 14 publications

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“…Beyond documenting this receptor-ligand interaction and defining the PVR family, it was clearly demonstrated that IL-10 induction via PVR is robust enough to inhibit antigen-specific T-cell responses. Additional studies in which the pathway is inhibited-either by blocking proteins or by gene ablation-support the TIGIT-PVR interaction as being important for setting the threshold for T-cell responses in both secondary lymph organs and mucosal sites (31,32). The predominant immuno-coreceptors on T cells are CTLA-4 and CD28, which engage the same ligands, B7-1 and B7-2, on antigen-presenting cells such as DCs (28,29,33); however, additional receptors, such as PD-1 and ICOS, have emerged as important receptors in the immune system to fine-tune T-cell effector functions and maintain T-cell tolerance (34).…”

Section: Discussionmentioning

confidence: 99%

“…PVR, together with TIGIT and other PVRfamily members, CD226 and CD96, similarly regulate immune responses. Engagement of PVR with TIGIT induces an anti-inflammatory response (4,31,32); conversely, PVR interaction with the lower-affinity receptor CD226 on T and NK cells promotes immune activation (19,20). This paradigm holds true for a number of paired, homologous ITIM/ITAM receptors on T and NK cells (35) where the inhibiting receptor has a high affinity and the activating receptor has a lower affinity for the shared binding molecule and implies that the activating receptor probably needs to outcompete the inhibiting interaction to convey a signal.…”

Section: Discussionmentioning

confidence: 99%

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Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell–cell adhesion and signaling mechanism that requires cis-trans receptor clustering

Stengel¹,

Harden-Bowles²,

Yu³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

162

159

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Nectins (nectin1-4) and Necls ] are Ig superfamily cell adhesion molecules that regulate cell differentiation and tissue morphogenesis. Adherens junction formation and subsequent cell-cell signaling is initiated by the assembly of higher-order receptor clusters of cognate molecules on juxtaposed cells. However, the structural and mechanistic details of signaling cluster formation remain unclear. Here, we report the crystal structure of poliovirus receptor (PVR)/Nectin-like-5/CD155) in complex with its cognate immunoreceptor ligand T-cell-Ig-and-ITIM-domain (TIGIT). The TIGIT/ PVR interface reveals a conserved specific "lock-and-key" interaction. Notably, two TIGIT/PVR dimers assemble into a heterotetramer with a core TIGIT/TIGIT cis-homodimer, each TIGIT molecule binding one PVR molecule. Structure-guided mutations that disrupt the TIGIT/ TIGIT interface limit both TIGIT/PVR-mediated cell adhesion and TIGIT-induced PVR phosphorylation in primary dendritic cells. Our data suggest a cis-trans receptor clustering mechanism for cell adhesion and signaling by the TIGIT/PVR complex and provide structural insights into how the PVR family of immunoregulators function.N ectins (nectin1-4) and nectin-like (Necl1-5) molecules are members of the large Ig superfamily (IgSF) of cell-surface receptors that play central roles in cell adhesion, cell movement, proliferation, and survival and contribute to the morphogenesis and differentiation of many cell and tissue types by inducing an intracellular signaling cascade (1-5). Nectins and Necls can function as both ligands and receptors and therefore are able to signal bidirectionally into juxtaposed cells (3,6). To mediate the formation of cell adherens junctions, a model suggests that the extracellular domains of these molecules form ligand-dependent homo-or heterodimers in trans (between molecules located on the same or opposite cell surfaces, respectively) and lateral homodimers in cis, creating a tight network of nectin zippers between juxtaposed cells (7,8). To date, structural and functional studies suggest a mechanism whereby the cis-homodimerization of a receptor on the same cell surface is followed by the formation of a trans-dimer between juxtaposed cells using identical protein interfaces. This assembly is noteworthy because it requires a rearrangement and breakup of the cis-homodimer followed by a transdimerization across the adherens junction. The cis-trans clustering is then initiated through another unknown protein interface, likely involving a different receptor domain.Several high-affinity homophilic trans-interactions have been described in detail for nectins/Necls and similar molecules (8-13). However, the structure and function of the presumably weaker lateral homophilic cis-dimers in cell adhesion and their role in intracellular signaling is not known. Because all structures solved to date are homodimers, it is unclear if they represent the cisor the trans-state. Thus, the question of how cis-trans heterodimerization drives cell adhesion and intracellular sign...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell–cell adhesion and signaling mechanism that requires cis-trans receptor clustering

Stengel¹,

Harden-Bowles²,

Yu³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

162

159

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“…11 TIGIT-deficient mice are more susceptible to autoimmune diseases. 14,15 However, the inhibitory mechanism mediated by TIGIT has not been elucidated.…”

mentioning

confidence: 99%

“…10,12 TIGIT can bind to PVR of human dendritic cells to enhance interleukin 10 (IL-10) production, which inhibits T-cell activation. 10 Kuchroo et al 14 showed that TIGIT harbors a T-cell-intrinsic inhibitory function to suppress T-cell activation.…”

mentioning

confidence: 99%

Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells

et al. 2012

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Activating and inhibitory receptors control natural killer (NK) cell activity. T-cell immunoglobulin and ITIM (immunoreceptor tyrosine-based inhibition motif) domain (TIGIT) was recently identified as a new inhibitory receptor on T and NK cells that suppressed their effector functions. TIGIT harbors the immunoreceptor tail tyrosine (ITT)-like and ITIM motifs in its cytoplasmic tail. However, how its ITT-like motif functions in TIGIT-mediated negative signaling is still unclear. Here, we show that TIGIT/PVR (poliovirus receptor) engagement disrupts granule polarization leading to loss of killing activity of NK cells. The ITT-like motif of TIGIT has a major role in its negative signaling. After TIGIT/PVR ligation, the ITT-like motif is phosphorylated at Tyr225 and binds to cytosolic adapter Grb2, which can recruit SHIP1 to prematurely terminate phosphatidylinositol 3-kinase (PI3K) and MAPK signaling, leading to downregulation of NK cell function. In support of this, Tyr225 or Asn227 mutation leads to restoration of TIGIT/PVR-mediated cytotoxicity, and SHIP1 silencing can dramatically abolish TIGIT/PVR-mediated killing inhibition. Meanwhile, normal cells are kept away from their cytotoxicity. Therefore, the discrimination between 'self' normal cells and 'nonself' abnormal cells has to be precisely recognized by NK cells. [5][6][7] A very large repertoire of receptors, both activating and inhibitory, is proved to be critical in NK cell function. The best-known inhibitory receptors of NK cells are the killer-cell immunoglobulin-like receptor family, whose physical ligands are MHC-I molecules that are expressed on self normal cells to protect them from NK cell lysis. 8 Other non-MHC-I inhibitory receptors, which do not associate with MHC-I molecules, are also expressed on NK cells. 9 However, their physiological and pathological significances have not been defined yet.T-cell immunoglobulin and ITIM domain (TIGIT) was recently identified as an inhibitory receptor that is expressed mainly on NK cells, activated CD4 and CD8 T cells. 10-12 TIGIT harbors one extracellular immunoglobulin domain, a type 1 transmembrane region, and an immunoglobulin tail tyrosine (ITT)-like phosphorylation motif followed by an ITIM (immunoreceptor tyrosine-based inhibition motif) of the cytoplasmic tail. 13 The physical ligands of TIGIT were identified as the poliovirus receptor (PVR, or CD155) and the PVRL2 (Nectin2, or CD112). 10,12 TIGIT can bind to PVR of human dendritic cells to enhance interleukin 10 (IL-10) production, which inhibits T-cell activation. 10 Kuchroo et al. 14 showed that TIGIT harbors a T-cell-intrinsic inhibitory function to suppress T-cell activation.Moreover, TIGIT can inhibit NK cell cytolysis through engagement with PVR or PVRL2. 11 TIGIT-deficient mice are more susceptible to autoimmune diseases. 14,15 However, the inhibitory mechanism mediated by TIGIT has not been elucidated.TIGIT contains a classical ITIM motif, which recruits either Src homology (SH) 2 domain-containing protein tyrosine phosphatases SHP1 and SHP...

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“…Furthermore, it is considered a novel immune checkpoint molecule 13. TIGIT negatively regulates T cell responses through the effect of cluster of differentiation (CD) 112 or CD155 on dendritic cells or through intrinsic inhibitory effects such as inhibition of T cell proliferation or suppression of cytokine production in CD4 + T cells 14. Recently, TIGIT + Tregs have been shown to selectively suppress Th1 and Th17 responses but not Th2 responses 15.…”

Section: Introductionmentioning

confidence: 99%

DW2008S and its major constituents from Justicia procumbens exert anti‐asthmatic effect via multitargeting activity

Youm

Lee

Choi

et al. 2018

J Cellular Molecular Medi

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Our previous study revealed that the ethanolic extract of Justicia procumbens ameliorates ovalbumin‐induced airway inflammation and airway hyper‐responsiveness in a mouse model of asthma. However, the mechanism of action of the extract remains unknown. In this study, we prepared DW2008S, an optimized and standardized powder extracted from J. procumbens using anhydrous ethanol, and investigated its anti‐asthmatic effect and mechanism of action. Our results showed that DW2008S contains two major ingredients, justicidin A (JA) and justicidin B (JB), which selectively inhibit T helper 2 (Th2) cell responses in concanavalin A‐activated spleen cells and polarized Th2 cells. Blockade of T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine‐based inhibition motif domains (TIGIT) using a neutralizing antibody also selectively inhibited Th2 cell responses. Furthermore, DW2008S regulated TIGIT expression in the mice and cultured cells. Additionally, DW2008S and JA antagonized human adenosine receptor A3 (A3 AR), which mediates mast cell‐dependent inflammation and bronchoconstriction. DW2008S and JB inhibited human phosphodiesterase 4 (PDE4), which is known to cause bronchoconstriction; however, the required concentrations were higher than those needed to affect TIGIT . These findings suggest that DW2008S can potentially ameliorate Th2‐driven airway inflammation and bronchoconstriction through negative regulation of TIGIT and blockade of A3 AR and PDE4 activities.

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Cutting Edge: TIGIT Has T Cell-Intrinsic Inhibitory Functions

Cited by 463 publications

References 14 publications

Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell–cell adhesion and signaling mechanism that requires cis-trans receptor clustering

Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell–cell adhesion and signaling mechanism that requires cis-trans receptor clustering

Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells

DW2008S and its major constituents from Justicia procumbens exert anti‐asthmatic effect via multitargeting activity

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