Mouse <scp>TIGIT</scp> inhibits <scp>NK</scp>‐cell cytotoxicity upon interaction with <scp>PVR</scp>

Stanietsky, Noa; Roviš, Tihana Lenac; Glasner, Ariella; Seidel, Einat; Tsukerman, Pinchas; Yamin, Rachel; Enk, Jonatan; Jonjić, Stipan; Mandelboim, Ofer

doi:10.1002/eji.201243072

Cited by 215 publications

(153 citation statements)

References 41 publications

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“…1C). We also stained for the inhibitory ligand CEACAM1, which interacts homophilically (49), and for PVR, which is recognized both by the activating receptor DNAM-1 and the inhibitory receptor TIGIT (50,51). However, in our hands, SupT1 cells did not express these molecules either prior to or following infection (data not shown).…”

Section: Expression Of Ligands For Several Activating Nk Receptors Ismentioning

confidence: 65%

Human Herpesvirus 6B Downregulates Expression of Activating Ligands during Lytic Infection To Escape Elimination by Natural Killer Cells

Schmiedel

Tai

Levi‐Schaffer

et al. 2016

J Virol

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The Herpesviridae family consists of eight viruses, most of which infect a majority of the human population. One of the lessstudied members is human herpesvirus 6 (HHV-6) (Roseolovirus), which causes a mild, well-characterized childhood disease. Primary HHV-6 infection is followed by lifelong latency. Reactivation frequently occurs in immunocompromised patients, such as those suffering from HIV infection or cancer or following transplantation, and causes potentially life-threatening complications. In this study, we investigated the mechanisms that HHV-6 utilizes to remain undetected by natural killer (NK) cells, which are key participants in the innate immune response to infections. We revealed viral mechanisms which downregulate ligands for two powerful activating NK cell receptors: ULBP1, ULBP3, and MICB, which trigger NKG2D, and B7-H6, which activates NKp30. Accordingly, this downregulation impaired the ability of NK cells to recognize HHV-6-infected cells. Thus, we describe for the first time immune evasion mechanisms of HHV-6 that protect lytically infected cells from NK elimination. IMPORTANCEHuman herpesvirus 6 (HHV-6) latently infects a large portion of the human population and can reactivate in humans lacking a functional immune system, such as cancer or AIDS patients. Under these conditions, it can cause life-threatening diseases. To date, the actions and interplay of immune cells, and particularly cells of the innate immune system, during HHV-6 infection are poorly defined. In this study, we aimed to understand how cells undergoing lytic HHV-6 infection interact with natural killer (NK) cells, innate lymphocytes constituting the first line of defense against viral intruders. We show that HHV-6 suppresses the expression of surface proteins that alert the immune cells by triggering two major receptors on NK cells, NKG2D and NKp30. As a consequence, HHV-6 can replicate undetected by the innate immune system and potentially spread infection throughout the body. This study advances the understanding of HHV-6 biology and the measures it uses to successfully escape immune elimination. Human herpesvirus 6 (HHV-6) (Roseolovirus) was long neglected in research and medical diagnostics; however, in the past few years, it gained increasing attention. A variety of clinical complications were found to be associated with HHV-6 infection, especially concerning immunocompromised patients, in whom it has the ability to cause severe morbidity and mortality (1, 2). HHV-6 is subclassified into two distinct variants, HHV-6A and HHV-6B, which are considered independent viruses but share major genome sequence homologies and epidemiologies (3,4). Similarly to other members of the herpesvirus family, HHV-6 causes a relatively short and mild primary disease called roseola infantum, usually in children up to the age of 2 years, with a sudden rise of fever and rash as major symptoms (5). Following this initial infection, HHV-6 establishes lifelong latency in about 90% of all individuals examined (2). Reactivation frequentl...

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Section: Expression Of Ligands For Several Activating Nk Receptors Ismentioning

confidence: 65%

Human Herpesvirus 6B Downregulates Expression of Activating Ligands during Lytic Infection To Escape Elimination by Natural Killer Cells

Schmiedel

Tai

Levi‐Schaffer

et al. 2016

J Virol

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“…Our study suggests that the expression of CD155 may represent a strong determinant of MM immunogenicity, and an extensive understanding of the clinical impact of this ligand expression in MM patients is now required. CD226 was also shown to interact with CD112 (48,49), but the relevance of CD112/CD226 interactions in mice remains unclear (50). Although, CD112 expression was usually low or absent on Vk*MYC MM cells, this ligand was found to be expressed on human MM cells and could also play a role in the pathogenesis of this disease (8).…”

Section: Anti-cd137 Immunotherapy Against Myeloma Requires Nk and Cd8mentioning

confidence: 99%

Immunosurveillance and therapy of multiple myeloma are CD226 dependent

Guillerey¹,

Andrade²,

Vučković³

et al. 2015

J. Clin. Invest.

114

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“…In addition to TIGIT expressed on T cells, TIGIT Ab blocks TIGIT on other cell types that mediate allergic responses (37). For example, TIGIT is highly expressed on NK cells and is an inhibitor of NK cell cytotoxicity (3,38,39). However, the role of TIGIT in NK2 cells that mediate asthma is unknown and merits investigation (40).…”

Section: Il-4-and Il-13-secreting Cd4mentioning

confidence: 99%

“…For these experiments, we used a TIGITspecific polyclonal Ab previously shown to effectively block TIGIT in vitro (38). We alternatively tested a mAb against TIGIT (1G9) that had no agonistic activity (7).…”

Section: Il-4-and Il-13-secreting Cd4mentioning

confidence: 99%

TIGIT Enhances Antigen-Specific Th2 Recall Responses and Allergic Disease

Kourepini

Paschalidis

Simoes

et al. 2016

The Journal of Immunology

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T cell Ig and ITIM domain receptor (TIGIT), expressed on T, NK, and regulatory T cells, is known as an inhibitory molecule that limits autoimmunity, antiviral and antitumor immunity. In this report, we demonstrate that TIGIT enhances Th2 immunity. TIGIT expression was upregulated in activated Th2 cells from mice with experimental allergic disease and in Th2 polarization cultures. In addition, its high-affinity ligand CD155 was upregulated in mediastinal lymph node dendritic cells from allergic mice. In an in vitro setting, we observed that Tigit expression in Th2 cells and its interaction with CD155 expressed in dendritic cells were important during the development of Th2 responses. In addition, blockade of TIGIT inhibited Th2, but had no effect on either Th1 or Th17 polarization. In vivo blockade of TIGIT suppressed hallmarks of allergic airway disease, such as lung eosinophilia, goblet cell hyperplasia, Ag-specific Th2 responses, and IgE production, and reduced numbers of T follicular helper and effector Th2 cells. Thus, TIGIT is critical for Th2 immunity and can be used as a therapeutic target, especially in light of recent findings showing TIGIT locus hypomethylation in T cells from pediatric patients with allergic asthma.

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Mouse TIGIT inhibits NK‐cell cytotoxicity upon interaction with PVR

Cited by 215 publications

References 41 publications

Human Herpesvirus 6B Downregulates Expression of Activating Ligands during Lytic Infection To Escape Elimination by Natural Killer Cells

Human Herpesvirus 6B Downregulates Expression of Activating Ligands during Lytic Infection To Escape Elimination by Natural Killer Cells

Immunosurveillance and therapy of multiple myeloma are CD226 dependent

TIGIT Enhances Antigen-Specific Th2 Recall Responses and Allergic Disease

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