The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells

Yu, Xin; Harden, Kristin; Gonzalez, Lino C.; Francesco, Michelle; Chiang, Eugene Y.; Irving, Bryan; Tom, Irene; Ivelja, Sinisa; Refino, Canio J.; Clark, Hilary; Eaton, Dan; Grogan, Jane L.

doi:10.1038/ni.1674

Cited by 1,149 publications

(1,491 citation statements)

References 47 publications

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“…Activation of the TIGIT pathway has been found to increase IL-10 and reduce IL-12 production by DCs, rendering a suppressive phenotype. 16 TIGIT blockade, therefore, could mitigate this effect and reduce IL-10 activation of effector T cells. Interestingly, TIGIT has not been found to change DC maturation (characterized by expression of CD80, CD86, CD83, and HLA-DR) in the in vitro setting, though it remains unclear how this observation may change in an in vivo model.…”

Section: Discussionmentioning

confidence: 99%

“…13-15 It is expressed on a variety of immune cells, including T cells, regulatory T cells (Tregs), and natural killer (NK) cells. 16 TIGIT competes with CD226, its co-stimulatory counterpart, to bind to the poliovirus receptor (PVR, also known as CD155) with higher affinity. 17 , 18 Elevated TIGIT expression on CD8 + T cells and Tregs has been shown to confer an overall suppressive phenotype, correlating with reduced cytokine production and poor survival in multiple cancer models.…”

Section: Introductionmentioning

confidence: 99%

“…19-22 Moreover, this effect was further suggested to be mediated by dendritic cells (DCs), which can regulate the TIGIT pathway via the expression of CD155. 16 In the clinical setting, prior studies have demonstrated an elevated expression of CD155 on human GBM cells and increased TIGIT expression on patient CD8 + tumor-infiltrating lymphocytes (TILs), rendering this pathway as a potential therapeutic target. 23 , 24 However, the effect of TIGIT blockade as a treatment strategy remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

et al. 2018

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The use of inhibitory checkpoint blockade in the management of glioblastoma has been studied in both preclinical and clinical settings. TIGIT is a novel checkpoint inhibitor recently discovered to play a role in cancer immunity. In this study, we sought to determine the effect of anti-PD-1 and anti-TIGIT combination therapy on survival in a murine glioblastoma (GBM) model, and to elucidate the underlying immune mechanisms. Using mice with intracranial GL261-luc+ tumors, we found that TIGIT expression was upregulated on CD8+ and regulatory T cells (Tregs) in the brain compared to draining cervical lymph nodes (CLN) and spleen. We then demonstrated that treatment using anti-PD-1 and anti-TIGIT dual therapy significantly improved survival compared to control and monotherapy groups. The therapeutic effect was correlated with both increased effector T cell function and downregulation of suppressive Tregs and tumor-infiltrating dendritic cells (TIDCs). Clinically, TIGIT expression on tumor-infiltrating lymphocytes was shown to be elevated in patient GBM samples, suggesting that the TIGIT pathway may be a valuable therapeutic target. Expression of the TIGIT ligand, PVR, further portended a poor survival outcome in patients with low-grade glioma. We conclude that anti-TIGIT is an effective treatment strategy against murine GBM when used in combination with anti-PD-1, improving overall survival via modifications of both the T cell and myeloid compartments. Given evidence of PVR expression on human GBM cells, TIGIT presents as a promising immune therapeutic target in the management of these patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

et al. 2018

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“…It is now clear that much complexity in the Treg phenotype exists than originally appreciated, and a growing number of other cell surface markers are found on specific Treg subsets, for example TIGIT,11, 12 GARP,13, 14, 15, 16 CD73 and CD39 17, 18. These markers are frequently also found on effector cell populations, and an emerging theme is that either Treg are able to transition between functional states or that the Treg compartment is paired with the Tconv effector compartment so that any immune response mediated by a T‐cell can be controlled by a matching Treg 19.…”

Section: Introduction: the Treg Phenotypementioning

confidence: 99%

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

et al. 2018

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Regulatory T cells (Treg) are critical for preventing autoimmunity and curtailing responses of conventional effector T cells (Tconv). The reprogramming of T‐cell fate and function to generate Treg requires switching on and off of key gene regulatory networks, which may be initiated by a subtle shift in expression levels of specific genes. This can be achieved by intermediary regulatory processes that include microRNA and long noncoding RNA‐based regulation of gene expression. There are well‐documented microRNA profiles in Treg and Tconv, and these can operate to either reinforce or reduce expression of a specific set of target genes, including FOXP3 itself. This type of feedforward/feedback regulatory loop is normally stable in the steady state, but can alter in response to local cues or genetic risk. This may go some way to explaining T‐cell plasticity. In addition, in chronic inflammation or autoimmunity, altered Treg/Tconv function may be influenced by changes in enhancer–promoter interactions, which are highly cell type‐specific. These interactions are impacted by genetic risk based on genome‐wide association studies and may cause subtle alterations to the gene regulatory networks controlled by or controlling FOXP3 and its target genes. Recent insights into the 3D organisation of chromatin and the mapping of noncoding regulatory regions to the genes they control are shedding new light on the direct impact of genetic risk on T‐cell function and susceptibility to inflammatory and autoimmune conditions.

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“…T cell immunoreceptor with Ig and immunoreceptor tyrosine‐based inhibition motif domains (TIGIT) is expressed on natural killer cells, memory T cells, activated T cells and regulatory T cells (Tregs). 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.…”

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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The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells

Cited by 1,149 publications

References 47 publications

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

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

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