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The activating receptor NKG2D and its ligands are recognized as a potent immune axis that controls tumor growth and microbial infections. With regards to cancer surveillance, various studies have demonstrated the antitumor function mediated by NKG2D on natural killer cells and on conventional and unconventional T cells. The use of NKG2D-deficient mice established the importance of NKG2D in delaying tumor development in transgenic mouse models of cancer. However, we recently demonstrated an unexpected, flip side to this coin, the ability for NKG2D to contribute to tumor growth in a model of inflammation-driven liver cancer. With a focus on the liver, here, we review current knowledge of NKG2D-mediated tumor surveillance and discuss evidence supporting a dual role for NKG2D in cancer immunity. We postulate that in certain advanced cancers, expression of ligands for NKG2D can drive cancer progression rather than rejection. We propose that the nature of the microenvironment within and surrounding tumors impacts the outcome of NKG2D activation. In a form of autoimmune attack, NKG2D promotes tissue damage, mostly in the inflamed tissue adjacent to the tumor, facilitating tumor progression while being ineffective at rejecting transformed cells in the tumor bed.

More than billion of obese and overweight people live currently in the world. A significant number of them develop diabetes mellitus type 2 (DM2) and non-alcoholic fatty liver disease (NAFLD). Mechanisms that induce inflammation and trigger transition from pre-diabetes to DM2 or from hepatic steatosis to non-alcoholic steatohepatitis (NASH) are still unclear. In this research I found that γδ T cells are enriched in visceral adipose tissue and they produce proinflammatory cytokines. In response to high fat diet (HFD), there is increase in number of γδ T cells that produce IL-17A. Research on NAFLD revealed that initiating event, in response to high calorie diet, is the increase in expression of the NKG2D ligand H60 on hepatocytes. Upregulation of ligands leads to mobilisation of γδ T cells through an NKG2D engagement that induces an increase in IL-17A. Lack of either γδ T cells, NKG2D or IL-17A significantly decreases development of liver fibrosis. Trenutno na svijetu živi više od milijarde pretilih ljudi i onih s prekomjernom težinom. Značajan broj njih obolijeva od šećerne bolesti tipa 2 (DM2) i nealkoholne bolesti masne jetre (NAFLD). Mehanizmi koji induciraju upalu u debljini i uzrokuju prijelaz iz stadija pre-dijabetesa u DM2 ili iz stadija jetrene steatoze u nealkoholni steatohepatitis (NASH) su još uvijek nejasni. U ovom istraživanju otkrila sam da se γδ limfociti T nalaze u velikom broju u visceralnom masnom tkivu i da mogu sintetizirati proupalne citokine. Kao odgovor na visoko-kalorijsku prehranu bogatu mastima dolazi do povećanja broja γδ limfocita T koji proizvode IL-17A. Istraživanja na NAFLD-u pokazala su da kao odgovor na visokokalorijsku dijetu, dolazi do povećanog izražaja NKG2D liganda H60 na hepatocitima. Povećani izražaj NKG2D liganda dovodi do mobilizacije γδ stanica kroz aktivaciju receptora NKG2D koji potiče sintezu IL-17A. Nedostatak γδ limfocita T, receptora NKG2D ili citokina IL-17A značajno smanjuje razvoj fibroze jetre.

Inflammation is recognized as one of the drivers of cancer. Yet, the individual immune components that possess pro- and anti-tumorigenic functions in individual cancers remain largely unknown. NKG2D is a potent activating immunoreceptor that has emerged as an important player in inflammatory disorders besides its well-established function as tumour suppressor. Here, we provide genetic evidence of an unexpected tumour-promoting effect of NKG2D in a model of inflammation-driven liver cancer. Compared to NKG2D-deficient mice, NKG2D-sufficient mice display accelerated tumour growth associated with, an increased recruitment of memory CD8+T cells to the liver and exacerbated pro-inflammatory milieu. In addition, we show that NKG2D contributes to liver damage and consequent hepatocyte proliferation known to favour tumorigenesis. Thus, the NKG2D/NKG2D-ligand pathway provides an additional mechanism linking chronic inflammation to tumour development in hepatocellular carcinoma. Our findings expose the need to selectively target the types of cancer that could benefit from NKG2D-based immunotherapy., Expression of NKG2D immunoreceptor ligands on tumour cells is believed to inhibit tumour growth through engaging NKG2D-expressing immune cells. Here, the authors show that in a model of liver cancer the NKG2D/NKG2D-ligand pathway can also promote tumour formation by sustaining an inflammatory environment.

An important role for natural killer (NK) cells in the regulation of T-cell responses is emerging, although the receptor pairs regulating the NK–T-cell interaction have still not been identified. We found that superantigen-stimulated T cells express Nectin-2 (CD112) and poliovirus receptor (PVR; CD155), the ligands of the activating NK receptor DNAX accessory molecule-1 (DNAM-1; CD226). Interestingly, only PVR was present at the T cell surface, particularly on cells in the S and G2/M phases of the cell cycle. The up-regulation of PVR expression involves DNA-damage response (DDR)–dependent pathways, because we found that pharmacologic inhibition of ATM and ATR kinases reduced PVR expression and that PVR was almost exclusively induced on cells expressing the DDR marker γH2AX. Oxidative stress contributed to DDR activation, and our results showed impaired PVR levels in the presence of the reactive oxygen species (ROS) scavenger N-acetyl-cysteine (NAC), being monocytes the main ROS source needed for optimal PVR expression on activated T cells. Interestingly, in accordance with ligand expression, NK cells lysed allogeneic proliferating more efficiently than nonproliferating T lymphocytes, with a mechanism requiring the cooperation between DNAM-1 and NKG2D. These results could contribute to unraveling the role of NK cells in the down-regulation of T-cell responses in physiologic and pathologic processes such as autoimmunity or GVHD.

NKG2D es un receptor activador expresado en las células naturales asesinas involucrado en la eliminación de células transformadas y/o infectadas por virus. Dentro de los ligandos descritos para este receptor están MICA y MICB y la familia de las ULBPs (ULBP1-ULBP6). Por otro lado, uno de los mecanismos de evasión por parte de la célula tumoral es el clivaje de éstas proteínas por parte de metaloproteinasas como ADAM10, ADAM17 y MMP14. Por lo anterior en este estudio analizamos la expresión de los ligandos y de las metaloproteinasas mencionadas anteriormente mediante PCR en tiempo real, en diferentes estadios: muestras con resultado de histopatología negativo, muestras con lesiones intraepiteliales de bajo grado y muestras con lesiones intraepiteliales de alto grado y en las líneas celulares HeLa y C-33 A. A pesar de que no se encontraron diferencias estadísticamente significativas para ninguno de los genes de estudio en los diferentes grupos si se observó una mayor expresión de las metaloproteinasas en la lesión de alto grado y en la línea celular HeLa. Para el caso de los ligandos en mica se observó una expresión baja en todos los grupos y en micb una mayor expresión en la lesión de bajo grado. Abstract. NKG2D is an activating receptor expressed by natural killer cells involved in the elimination of transformed and/or infected cells. Within the ligands described for this receptor are the related MHC class I molecules, MICA and MICB, and the ULBPs family (ULBP1-ULBP6). On the other hand, one of the mechanisms of tumor evasion is the NKG2D ligands shedding by metalloproteinases like ADAM10, ADAM17 y MMP14. Thus, in this study, we analyzed the expression of NKG2D ligands and metalloproteinases by real time PCR in different stages: Negative samples, samples with low grade and high grade lesions and in the cell lines HeLa and C-33 A. Although no statistically significant differences for any of the genes studied in the different groups, a high expression of metalloproteinases expression was observed in high grade lesion samples and in HeLa cell line. Low expression for mica was observed in all groups studied and an incresead micb expression in low grade lesion samples. Maestría

U nadzoru citomegalovirusnih (CMV) infekcija posredovanom NK-stanicama važnu ulogu ima aktivacijski receptor NKG2D. Njegovo vezivanje za ligande ispoljene na površini inficiranih stanica rezultira aktivacijom NK-stanica i citotoksičnošću. Jedan od mehanizama kojima CMV-i izbjegavaju NK-stanični nadzor je uklanjanje NKG2D liganada s membrane inficiranih stanica. Identificirana su tri mišja NKG2D liganda: RAE-1, H60 i MULT-1. Ranije je pronađeno da m152/gp40 MCMV-a onemogućuje površinsko ispoljavanje RAE-1, a mi u ovom radu pokazujemo da proteini m145 i m155 sprečavaju membransku ekspresiju H60 i MULT-1.