NKG2D ligands: key targets of the immune response

González, Segundo; López‐Soto, Alejandro; Suárez-Álvarez, Beatriz; López-Vázquez, Antonio; López‐Larrea, Carlos

doi:10.1016/j.it.2008.04.007

Cited by 220 publications

(199 citation statements)

References 72 publications

(130 reference statements)

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“…83,99 All-transretinoic acid and the histone deacetylase inhibitor sodium valproate were repeatedly shown to induce NKG2D ligand expression in certain types of tumors, including AML, 44,100,101 leading to an improved sensitivity to NK cell-mediated killing. Promotors of myeloid cell differentiation trichostatin A and vitamin D3 were also shown to upregulate NKG2D ligands on AML cells.…”

Section: Nk Cell Immune Escape In Aml E Lion Et Almentioning

confidence: 99%

Natural killer cell immune escape in acute myeloid leukemia

et al. 2012

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Section: Nk Cell Immune Escape In Aml E Lion Et Almentioning

confidence: 99%

Natural killer cell immune escape in acute myeloid leukemia

et al. 2012

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“…The ligands for the NKG2D receptor include RAE1 (RAE1α-RAE1ε), Mult1 and H60 in the mouse, and MICA/B and RAET1, also known as UL-16 binding proteins (ULBPs), in the human (14,15). Results of previous studies showed that NKG2D may function as a costimulatory receptor for both mouse and human CD8 + T cells (16,17).…”

Section: Cytotoxic Cd8mentioning

confidence: 99%

IL-15, in synergy with RAE-1ɛ, stimulates TCR-independent proliferation and activation of CD8+ T cells

Zhang

Pan

et al. 2011

Oncology Letters

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Abstract. CD8+ T cells play critical roles in immunosurveil lance by killing malignant or virally infected cells. Interleukin 15 (IL-15) is a critical cytokine for promoting proliferation and the effector capacity of CD8 + T cells, and has been used to support the growth of CD8 + T cells in cellular therapies of neoplastic diseases. Recent studies have shown that IL-15, in synergy with other cytokines, such as IL-6, enhances the T-cell receptor (TCR)-independent proliferation and function of CD8 + T cells. The aim of the present study was to investigate the role of BaF3-mb15-RAE cells in stimulating mouse CD8 + T cells. BaF3 cells were cultured and B16F10 cells were grown in DMEM. MTT assay was used to detect the proliferation of CD8 + T cells. Cells were analyzed using flow cytometry. The results showed that IL-15 synergistically acts with another T-cell stimulatory molecule, RAE1ε, to potently promote the proliferation of CD8 + T cells, induce CD8 + T-cell activation and enhance granzyme B and interferon-γ (IFN-γ) production in the absence of signaling via the TCR. Moreover, IL-15 in combination with RAE1ε resulted in a cooperative effect on CD8 + T-cell-mediated cytotoxicity against B16F10 tumor cells. Thus, results of the present study showed that IL-15, in synergy with RAE1ε, enhances the TCR-independent effector function of CD8 + T cells in vitro, which may be useful in the cellular immunotherapy of cancer. Introduction Cytotoxic CD8+ T cells are effector cells that play a key role in immunosurveillance through the elimination of malignant or virally infected cells. Interleukin 15 (IL-15) is a pivotal cytokine for the activation and proliferation of cytotoxic CD8 + T cells (1-3). As opposed to other soluble cytokines that induce signals upon binding to their respective receptors, IL-15 delivery is relatively unique (4). IL-15 bound to its high-affinity receptor (IL-15R)α-chain may be retained on the cell surface and presented in trans to target cells such as CD8 + T cells, which express only IL-2/15Rβ and γ (5). The receptor-cytokine complex may act as a membrane-bound stimulatory molecule in a contact-dependent manner (6). Numerous studies raised the possibility that the IL-15/IL-15Rα complex is a promising and potent agent for tumor immunotherapy (7-11).NKG2D is an activating receptor present on the surface of mouse and human NK, γδT, human CD8 + T and activated mouse CD8 + T cells (12,13). The ligands for the NKG2D receptor include RAE1 (RAE1α-RAE1ε), Mult1 and H60 in the mouse, and MICA/B and RAET1, also known as UL-16 binding proteins (ULBPs), in the human (14,15). Results of previous studies showed that NKG2D may function as a costimulatory receptor for both mouse and human CD8 + T cells (16,17). IL-15 selectively upregulates the expression and function of NKG2D (18). In addition, IL-15 confers NK-like activity to effector CD8 + T cells, unveiling the cytotoxic properties of NKG2D (18).Since NKG2D and IL-15 play significant roles in the activation and/or expansion of CD8 + T cells (as mentioned above...

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“…In humans, NKG2D is the receptor for MHC class I chain-related molecules A and B (MICA/B) and ULBP molecules, whose expression is restricted in benign cells, whereas it is upregulated in infected and transformed cells (11,12). Tumor cells expressing NKG2D ligands (NKG2DLs) become susceptible to an immune-dependent rejection mainly mediated by NK and T cells (13). NKG2D response may protect the host in the first stages of tumor development, at least in part, because activation of ataxia telangiectasia mutated pathway upregulates NKG2DL expression in malignant cells (14,15).…”

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confidence: 99%

Epithelial–Mesenchymal Transition Induces an Antitumor Immune Response Mediated by NKG2D Receptor

López‐Soto

Huergo-Zapico

Galván

et al. 2013

The Journal of Immunology

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Epithelial–mesenchymal transition (EMT) is a morphogenetic process characterized by the acquisition of mesenchymal properties linked with an invasive phenotype and metastasis of tumor cells. NK group 2, member D (NKG2D) is an NK cell–activating receptor crucially involved in cancer immunosurveillance. In this study, we show that induction of EMT by TGF-β stimulation of human keratinocytes, by glycogen synthase kinase-3β inhibition in several epithelial tumor cell lines, and by Snail1 overexpression in colorectal cancer cells strongly upregulated the expression of NKG2D ligands (NKG2DLs), MHC class I chain–related molecules A and B (MICA/B) and ULBP1-3. Overexpression of Snail1 and inhibition of glycogen synthase kinase-3β in colorectal tumor cells markedly induced the activity of Sp1 transcription factor, which plays a key role in the upregulation of NKG2DL expression during EMT. The stimulation of MICA/B expression by TGF-β treatment was independent of Sp1, but it involved posttranslational mechanisms mediated by mammalian target of rapamycin pathway. Accordingly, with the increased expression of NKG2DLs, triggering of EMT rendered cancer cells more susceptible to NKG2D-mediated killing by NK cells. In agreement, MICA/B were expressed in vivo in well-differentiated colorectal tumors with retained epithelial characteristics, whereas no expression of MICA/B was detected in poorly differentiated and invasive colorectal tumors that have lost epithelial characteristics. This decrease of MICA/B expression was associated with a dramatic increase of NKG2D+-tumor infiltrating lymphocytes. Overall, our findings indicate that EMT is a relevant checkpoint in the control of tumor progression through NKG2D-mediated immune responses.

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NKG2D ligands: key targets of the immune response

Cited by 220 publications

References 72 publications

Natural killer cell immune escape in acute myeloid leukemia

Natural killer cell immune escape in acute myeloid leukemia

IL-15, in synergy with RAE-1ɛ, stimulates TCR-independent proliferation and activation of CD8+ T cells

Epithelial–Mesenchymal Transition Induces an Antitumor Immune Response Mediated by NKG2D Receptor

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