NK cell cytotoxicity is controlled by numerous NK inhibitory and activating receptors. Most of the inhibitory receptors bind MHC class I proteins and are expressed in a variegated fashion. It was recently shown that TIGIT, a new protein expressed by T and NK cells binds to PVR and PVR-like receptors and inhibits T cell activity indirectly through the manipulation of DC activity. Here, we show that TIGIT is expressed by all human NK cells, that it binds PVR and PVRL2 but not PVRL3 and that it inhibits NK cytotoxicity directly through its ITIM. Finally, we show that TIGIT counter inhibits the NK-mediated killing of tumor cells and protects normal cells from NK-mediated cytoxicity thus providing an ''alternative self'' mechanism for MHC class I inhibition.inhibitory receptors ͉ natural killers I n contrast to T cells, that possess a single dominant antigen receptor (1), NK cells rely on a vast combinatorial array of receptors to initiate effector functions (2). Both activating and inhibitory receptors expressed on NK cells regulate their activity when interacting with tumors, virus infected cells and bacteria, as well as normal self-cells (2). MHC class I-expressing cells are protected from NK-mediated lysis due to the recognition of various MHC class I proteins by the inhibitory receptors KIR, LIR and CD94-NKG2A (3). Other NK inhibitory receptors which do not interact with MHC class I also exist, such as CEACAM1 and IRp60 (4-8). The significance, however, of these non-MHC class I inhibitory receptors in normal conditions is still unclear. All of the inhibitory receptors share a common immune receptor tyrosinebased inhibitory motif (ITIM) in their cytoplasmic regions, which delivers the inhibitory signal (3).The NK cell-mediated killing is extracted by specific receptors, among which are the natural cytotoxicity receptors (NCRs), which include the NKp30 that interacts with pp65 of human cytomegalovirus (CMV), BAT3 and the recently identified B7-family member B7-H6 (9-11), and the NKp46/NKp44 receptors, which interact with various viral hemagglutinins (12, 13). The NKG2D receptor interacts with MICA, MICB and ULBP 1-5 (14) and NKp80 interacts with AICL (15). In addition, two other receptors, DNAM-1 and CD96, enhance NK cytotoxicity (16,17). Both DNAM-1 and CD96 recognize PVR (CD155), whereas DNAM-1 also recognizes PVRL2 (CD112) (16,17). It was recently shown that a new receptor, named TIGIT, for T cell Ig and ITIM domain, interacts with PVR and its related proteins and that TIGIT inhibits T cell activity indirectly through the manipulation of DC activity (18). Here, we show that TIGIT, through its ITIM, can directly inhibit NK cytotoxicity. ResultsTIGIT Inhibits YTS Killing Through Its ITIM Motif. While searching for new CD28 family-like receptors, based on bioinformatics analysis, we observed that a protein named VSIG9 or VSTM3 in the databases expresses an ITIM motif. We continued to work on this protein and found that it interacts with PVR (CD155) but not with any other NK ligands tested (supporting information (...

The elimination of viruses and tumors by natural killer cells is mediated by specific natural killer cell receptors. To study the in vivo function of a principal activating natural killer cell receptor, NCR1 (NKp46 in humans), we replaced the gene encoding this receptor (Ncr1) with a green fluorescent protein reporter cassette. There was enhanced spread of certain tumors in 129/Sv but not C57BL/6 Ncr1(gfp/gfp) mice, and influenza virus infection was lethal in both 129/Sv and C57BL/6 Ncr1(gfp/gfp) mice. We noted accumulation of natural killer cells at the site of influenza infection by tracking the green fluorescent protein. Our results demonstrate a critical function for Ncr1 in the in vivo eradication of influenza virus.

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We report a case of monkeypox in a man who returned from Nigeria to Israel in 2018. Virus was detected in pustule swabs by transmission electron microscopy and PCR and confirmed by immunofluorescence assay, tissue culture, and ELISA. The West Africa monkeypox outbreak calls for increased awareness by public health authorities worldwide.

Human cytomegalovirus, a chief pathogen in immunocompromised people, can persist in a healthy immunocompetent host throughout life without being eliminated by the immune system. Here we show that pp65, the main tegument protein of human cytomegalovirus, inhibited natural killer cell cytotoxicity by an interaction with the activating receptor NKp30. This interaction was direct and specific, leading to dissociation of the linked CD3zeta from NKp30 and, consequently, to reduced killing. Thus, pp65 is a ligand for the NKp30 receptor and demonstrates a unique mechanism by which an intracellular viral protein causes general suppression of natural killer cell cytotoxicity by specific interaction with an activating receptor.

The mechanism of action of natural killer (NK) cells in type 1 diabetes is still unknown. Here we show that the activating receptor NKp46 recognizes mouse and human ligands on pancreatic beta cells. NK cells appeared in the pancreas when insulitis progressed to type 1 diabetes, and NKp46 engagement by beta cells led to degranulation of NK cells. NKp46-deficient mice had less development of type 1 diabetes induced by injection of a low dose of streptozotocin. Injection of soluble NKp46 proteins into nonobese diabetic mice during the early phase of insulitis and the prediabetic stage prevented the development of type 1 diabetes. Our findings demonstrate that NKp46 is essential for the development of type 1 diabetes and highlight potential new therapeutic modalities for this disease.

The COVID-19 pandemic caused by SARS-CoV-2 imposes an urgent need for rapid development of an efficient and cost-effective vaccine, suitable for mass immunization. Here, we show the development of a replication competent recombinant VSV-∆G-spike vaccine, in which the glycoprotein of VSV is replaced by the spike protein of SARS-CoV-2. In-vitro characterization of this vaccine indicates the expression and presentation of the spike protein on the viral membrane with antigenic similarity to SARS-CoV-2. A golden Syrian hamster in-vivo model for COVID-19 is implemented. We show that a single-dose vaccination results in a rapid and potent induction of SARS-CoV-2 neutralizing antibodies. Importantly, vaccination protects hamsters against SARS-CoV-2 challenge, as demonstrated by the abrogation of body weight loss, and  alleviation of the extensive tissue damage and viral loads in lungs and nasal turbinates. Taken together, we suggest the recombinant VSV-∆G-spike as a safe, efficacious and protective vaccine against SARS-CoV-2.