{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n KLRK1 (also known as NKG2D) is a key activating immunoreceptor expressed primarily on natural killer (NK) cells as well as on subsets of T lymphocytes (including CD8⁺ and γδ T cells). Its engagement by a panel of stress‐induced self‐ligands – such as the major histocompatibility complex class I–related proteins (MICA and MICB) and the UL16‐binding proteins (ULBPs) – is critical for triggering cytotoxicity and cytokine secretion. This receptor not only promotes immediate innate killing of transformed or infected cells but also acts as a costimulatory signal for antigen‐specific T cells, thereby bridging innate and adaptive immunity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n KLRK1 transduces its signals primarily through its association with the adaptor protein DAP10, which activates downstream effectors – including phosphatidylinositol 3-kinase and Vav1 – independently of classical ITAM-mediated (immunoreceptor tyrosine-based activation motif) pathways. This signaling cascade is essential for NK cell activation, proliferation, and effective tumor cell lysis, and it also contributes to the costimulation of CD8⁺ T cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n The function and efficacy of KLRK1 are further modulated by processes in the tumor microenvironment. For instance, proteolytic shedding of its ligands (e.g. MICA) – a process that may involve protein disulphide isomerases and ADAM family proteases – can lead to decreased receptor expression and impaired NK cell function, thereby contributing to tumor immune evasion. In addition, viral factors such as microRNAs can downregulate the expression of these ligands, further subverting KLRK1-mediated cytotoxic responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, KLRK1 plays a central role in immunosurveillance by sensing cellular stress and transformation. Its ability to initiate NK cell cytotoxicity and costimulate T-cell responses makes KLRK1 a pivotal component in host defense against tumors and infections, as well as a promising target for immunotherapeutic strategies.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Veronika Groh, Jennifer Wu, Cassian Yee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature01112"}], "href": "https://doi.org/10.1038/nature01112"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12384702"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12384702"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "David H Raulet "}, {"type": "b", "children": [{"type": "t", "text": "Roles of the NKG2D immunoreceptor and its ligands."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Rev Immunol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nri1199"}], "href": "https://doi.org/10.1038/nri1199"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14523385"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14523385"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Grazia Maria Spaggiari, Andrea Capobianco, Heba Abdelrazik, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2007-02-074997"}], "href": "https://doi.org/10.1182/blood-2007-02-074997"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17951526"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17951526"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "David H Raulet, Stephan Gasser, Benjamin G Gowen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of ligands for the NKG2D activating receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Annu Rev Immunol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1146/annurev-immunol-032712-095951"}], "href": "https://doi.org/10.1146/annurev-immunol-032712-095951"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23298206"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23298206"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Nadia Guerra, Ying Xim Tan, Nathalie T Joncker, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunity (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.immuni.2008.02.016"}], "href": "https://doi.org/10.1016/j.immuni.2008.02.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18394936"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18394936"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Amanda M Jamieson, Andreas Diefenbach, Christopher W McMahon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The role of the NKG2D immunoreceptor in immune cell activation and natural killing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunity (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s1074-7613(02)00333-3"}], "href": "https://doi.org/10.1016/s1074-7613(02"}, {"type": "t", "text": "00333-3) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12150888"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12150888"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Daniela Pende, Paola Rivera, Stefania Marcenaro, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Major histocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lines of different histotypes: analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2002)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12414645"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12414645"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Brett K Kaiser, Daesong Yim, I-Ting Chow, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Disulphide-isomerase-enabled shedding of tumour-associated NKG2D ligands."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature05768"}], "href": "https://doi.org/10.1038/nature05768"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17495932"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17495932"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Noam Stern-Ginossar, Naama Elefant, Albert Zimmermann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Host immune system gene targeting by a viral miRNA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1140956"}], "href": "https://doi.org/10.1126/science.1140956"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17641203"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17641203"}]}]}]}