The human NKG2D ligand ULBP2 can be expressed at the cell surface with or without a GPI anchor and both forms can activate NK cells

Fernández-Messina, Lola; Ashiru, Omodele; Agüera-González, Sonia; Reyburn, Hugh; Valés‐Gómez, Mar

doi:10.1242/jcs.076042

Cited by 29 publications

(35 citation statements)

References 39 publications

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“…The ULBP1-3 molecules are all anchored to the plasma membrane via a glycosylphophatidylinositol (GPI) domain. However, it has been shown that ULBP2, but not ULBP1 and 3, can relocate to the cell surface in the absence of a GPI moiety as a transmembrane protein that allows for more stable interaction with NKG2D receptors on NK cells (28). Moreover, soluble levels of ULBP2 have been correlated with reduced survival in patients with cancer, which has not been shown for other NKG2D ligands (29).…”

Section: Discussionmentioning

confidence: 97%

Human Anaplastic Thyroid Carcinoma Cells Are Sensitive to NK Cell–Mediated Lysis via ULBP2/5/6 and Chemoattract NK Cells

Wennerberg

Pfefferle

Ekblad

et al. 2014

Clinical Cancer Research

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Purpose: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive forms of cancer with no curative therapies available. To date, strategies to target ATC by immunotherapy have not been evaluated. We investigated whether ATC would be a suitable target for natural killer (NK) cell-based immunotherapy.Experimental Design: We first established seven new cell lines from ATC tumors, three from papillary thyroid carcinoma tumors and analyzed them together with eight additional ATC cell lines. Cells were analyzed for sensitivity to lysis by NK cells and their ability to chemoattract and regulate the activity of NK cells. In addition, fresh tumor samples and peripheral blood from six patients with ATC were analyzed for NK cell infiltration and phenotype.Results: We observed that ATC cell lines are sensitive to lysis by ex vivo expanded NK cells and that the lysis was abrogated upon blockade of NKG2D. Sensitivity of thyroid cancer cell lines to NK cell-mediated lysis correlated with surface expression of UL16-binding protein 2 on tumor cells. Moreover, ATC cell lines produced high levels of CXCL10 and stimulated migration of expanded NK cells and ATC tumors were enriched for NK cells expressing the cognate chemokine receptor CXCR3. However, compared with NK cells in peripheral blood, ATC tumor-derived NK cells displayed a suppressed phenotype with a downregulated expression of NKG2D. In vitro, suppression of NK cell-mediated lysis and NKG2D expression by ATC cells was restored upon neutralization of prostaglandin-E2.Conclusions: ATC cell lines are sensitive to NK cell-mediated lysis via ULBP2/5/6 and chemoattract CXCR3-positive NK cells. Patients with ATC may benefit from NK cell-based immunotherapy. Clin Cancer Res; 20(22); 5733-44. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 97%

Human Anaplastic Thyroid Carcinoma Cells Are Sensitive to NK Cell–Mediated Lysis via ULBP2/5/6 and Chemoattract NK Cells

Wennerberg

Pfefferle

Ekblad

et al. 2014

Clinical Cancer Research

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“…Human ULBP1–3 and 6 and mouse RAE1α–ε and H60c are GPI-linked, whereas human ULBP4–5 and mouse MULT1 and H60a and b are transmembrane proteins. In some cases (e.g., ULBP2 and possibly others), both GPI-linked and transmembrane forms of the protein are found on the same cell (22). The original image was kindly provided by Dr. Roland Strong of the Fred Hutchinson Cancer Research Center.…”

Section: Figurementioning

confidence: 99%

Regulation of Ligands for the NKG2D Activating Receptor

Raulet

Gasser²,

Gowen³

et al. 2013

Annu. Rev. Immunol.

679

823

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NKG2D is an activating receptor expressed by all NK cells and subsets of T cells. It serves as a major recognition receptor for detection and elimination of transformed and infected cells and participates in the genesis of several inflammatory diseases. The ligands for NKG2D are self-proteins that are induced by pathways that are active in certain pathophysiological states. NKG2D ligands are regulated transcriptionally, at the level of mRNA and protein stability, and by cleavage from the cell surface. In some cases, ligand induction can be attributed to pathways that are activated specifically in cancer cells or infected cells. We review the numerous pathways that have been implicated in the regulation of NKG2D ligands, discuss the pathologic states in which those pathways are likely to act, and attempt to synthesize the findings into general schemes of NKG2D ligand regulation in NK cell responses to cancer and infection.

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“…The RAET1 genes demonstrate less allelic polymorphism than the MICA and MICB genes. MICA, MICB, RAET1E (ULBP4), and RAET1G (ULBP5) are transmembrane-anchored glycoproteins, whereas RAET1I (ULBP1), RAET1H (ULBP2), RAET1N (ULBP3), and RAET1L (ULBP6) are glycophosphatidylinositol (GPI)-anchored, although RAET1H (ULBP2) may be expressed in both transmembrane-anchored and GPI-anchored forms (28) and RAET1G (ULBP5) may be GPI-anchored (29). Mice have orthologs of the human RAET1 genes present on mouse chromosome 10, but none of the mouse ligand genes correspond to MICA or MICB or are encoded within the mouse MHC.…”

Section: Nkg2d Ligand Genes and Proteinsmentioning

confidence: 99%

NKG2D Receptor and Its Ligands in Host Defense

Lanier

2015

Cancer Immunology Research

468

440

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NKG2D is an activating receptor expressed on the surface of natural killer (NK) cells, CD8+ T cells, and subsets of CD4+ T cells, iNKT cells, and γδ T cells. In humans NKG2D transmits signals by its association with the DAP10 adapter subunit and in mice alternatively spliced isoforms transmit signals either using DAP10 or DAP12 adapter subunits. Although NKG2D is encoded by a highly conserved gene (KLRK1) with limited polymorphism, the receptor recognizes an extensive repertoire of ligands, encoded by at least 8 genes in humans (MICA, MICB, RAET1E, RAET1G, RAET1H, RAET1I, RAET1L, and RAET1N), some with extensive allelic polymorphism. Expression of the NKG2D ligands is tightly regulated at the level of transcription, translation, and post-translation. In general healthy adult tissues do not express NKG2D glycoproteins on the cell surface, but these ligands can be induced by hyper-proliferation and transformation, as well as when cells are infected by pathogens. Thus, the NKG2D pathway serves a mechanism for the immune system to detect and eliminate cells that have undergone “stress”. Viruses and tumor cells have devised numerous strategies to evade detection by the NKG2D surveillance system and diversification of the NKG2D ligand genes likely has been driven by selective pressures imposed by pathogens. NKG2D provides an attractive target for therapeutics in the treatment of infectious diseases, cancer, and autoimmune diseases.

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The human NKG2D ligand ULBP2 can be expressed at the cell surface with or without a GPI anchor and both forms can activate NK cells

Cited by 29 publications

References 39 publications

Human Anaplastic Thyroid Carcinoma Cells Are Sensitive to NK Cell–Mediated Lysis via ULBP2/5/6 and Chemoattract NK Cells

Human Anaplastic Thyroid Carcinoma Cells Are Sensitive to NK Cell–Mediated Lysis via ULBP2/5/6 and Chemoattract NK Cells

Regulation of Ligands for the NKG2D Activating Receptor

NKG2D Receptor and Its Ligands in Host Defense

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