Beyond Stressed Self: Evidence for NKG2D Ligand Expression on Healthy Cells

Eagle, Robert A.; Jafferji, Insiya; Barrow, Alexander D.

doi:10.2174/157339509787314369

Cited by 78 publications

(75 citation statements)

References 117 publications

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“…There is also an emerging body of work reporting the expression of NKG2D ligands on healthy cells [24]. For example, NKG2D ligand expression was shown on activated T cells in both mouse and human, possibly representing a mechanism by which NK cells restrict excessive T-cell immune responses [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

“…The importance of NKG2D in antiviral immune responses is illustrated by the fact that many viruses have evolved one, and . Therefore, NKG2D has been described as participating in ''stressed'' or ''damaged self'' recognition [22,23].There is also an emerging body of work reporting the expression of NKG2D ligands on healthy cells [24]. For example, NKG2D ligand expression was shown on activated T cells in both mouse and human, possibly representing a mechanism by which NK cells restrict excessive T-cell immune responses [25][26][27].…”

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confidence: 99%

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ULBP6/RAET1L is an additional human NKG2D ligand

Eagle¹,

Traherne²,

Hair³

et al. 2009

Eur J Immunol

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106

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To date five ULBP/RAET (UL16-binding protein, also known as retinoic acid early transcript) genes, encoded on human chromosome 6q24.2-q25.3, have been shown to encode ligands of the activating immunoreceptor NKG2D. Here, we show that a sixth gene, ULBP6/RAET1L, is a polymorphic locus that expresses a functional transcript. ULBP6 had a more restricted expression profile in cell lines and primary human tissues than other NKG2D ligands, but expression was detected in several human papillomavirus-positive cervical carcinoma cell lines and was inducible on infection with human CMV. ULBP6 bound to recombinant NKG2D as well as the human CMV immune evasion molecule UL16. By confocal microscopy we show that UL16 retains ULBP6 inside the cell, preventing it from reaching the cell surface. Expression of ULBP6 on target cells induced a significant increase in NK-cell killing. Comparison of ULBP6 with ULBP4 and ULBP5 indicated that differences in recombinant NKG2D binding correlated with differences in NK-cell activation.Key words: Immune evasion . Infectious diseases . Innate immunity . NK cells . NK-cell ligandsSupporting Information available online IntroductionThe stimulatory immune receptor NKG2D (NK group 2, member D) plays an important role in anti-pathogen and anti-cancer immune responses [1]. In humans, NKG2D is expressed by all NK cells and almost all abT cells and gdT cells [1]. It is normally absent from CD4 1 T cells but can be induced in some circumstances, such as in rheumatoid arthritis patients [2] and on exposure to human CMV (HCMV) [3]. NKG2D signalling function is mediated exclusively through the adaptor molecule DAP10 in humans [4], whereas mouse NKG2D can associate with both DAP10 and DAP12 [5,6]. The downstream effects of NKG2D ligation are now recognised to depend on synergy with other cell surface receptors and cytokines, with IL-15 signalling recently being shown to have a particularly close association with the NKG2D-DAP10 complex [7,8].NKG2D ligands are a diverse array of cellular proteins, all of which have structural similarity to MHC class I molecules [9]. In humans NKG2D ligands are encoded in two gene families, MIC (MHC-class-I-polypeptide related sequence) and ULBP/RAET (UL16-binding protein, also known as retinoic acid early transcript) [10][11][12][13]. We will follow the ULBP nomenclature from this point. In mouse, NKG2D ligands comprise three members of the H60 family, five members of the Rae1 (retinoic acid early inducible transcript-1) family, and Mult-1 (murine ULBP-like transcript) [14][15][16][17].According to the initial models of NKG2D function, its ligands were thought to be largely absent from healthy cells, but their expression could be induced on viral infection and on tumourigenesis [1]. Ectopic expression of NKG2D ligand leads to anticancer immune responses to transplanted tumours in mice, and the NKG2D knockout mouse has an increased susceptibility to certain types of cancer [18][19][20]. The importance of NKG2D in antiviral immune responses is illustrated by the fact that ...

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

ULBP6/RAET1L is an additional human NKG2D ligand

Eagle¹,

Traherne²,

Hair³

et al. 2009

Eur J Immunol

Self Cite

106

View full text Add to dashboard Cite

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“…Humans express at least eight NKG2D ligands (NKG2DLs): MICA/B, ULBP1-3, RAET1E (ULBP4), RAET1G (ULBP5), and RAET1L (ULBP6). The ligands can be expressed independently of each other but are generally poorly expressed on normal, uninfected tissues (25). Because expression of these ligands is induced by infection (26), HCMV must prevent their upregulation to minimize their effects.…”

mentioning

confidence: 99%

Intracellular Sequestration of the NKG2D Ligand ULBP3 by Human Cytomegalovirus

Bennett¹,

Ashiru²,

Morgan³

et al. 2010

The Journal of Immunology

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Human CMV (HCMV) encodes multiple genes that control NK cell activation and cytotoxicity. Some of these HCMV-encoded gene products modulate NK cell activity as ligands expressed at the cell surface that engage inhibitory NK cell receptors, whereas others prevent the infected cell from upregulating ligands that bind to activating NK cell receptors. A major activating NKR is the homodimeric NKG2D receptor, which has eight distinct natural ligands in humans. It was shown that HCMV is able to prevent the surface expression of five of these ligands (MIC A/B and ULBP1, 2, and 6). In this article, we show that the HCMV gene product UL142 can prevent cell surface expression of ULBP3 during infection. We further show that UL142 interacts with ULBP3 and mediates its intracellular retention in a compartment that colocalizes with markers of the cis-Golgi complex. In doing so, UL142 prevents ULBP3 trafficking to the surface and protects transfected cells from NK-mediated cytotoxicity. This is the first description of a viral gene able to mediate downregulation of ULBP3.

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“…In NK cells, NKG2D functions as the primary activating receptor, while in T cells it acts as a co-stimulatory receptor that reinforces TCR-mediated activation (15)(16)(17). Consequently, NKG2D/NKG2DLs system may represent an important activation to begin a strong immune response to malignant cells (18).…”

Section: Introductionmentioning

confidence: 99%

Decline in peripheral blood NKG2D+CD3+CD56+ NKT cells in metastatic colorectal cancer patients

Gharagozloo¹,

Rezaei²,

Kalantari³

et al. 2018

BLL

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OBJECTIVE: Colorectal cancer (CRC) is one of the main causes of cancer deaths in the world. This cancer can be divided into non-metastatic and metastatic CRC stages. CD3+CD56+ NKT cell subsets are a minor T cell subset in peripheral blood and conduct the killing of tumor cells in direct manner. Little is obvious about levels and surface markers of these cells such as NKG2D in different cancers, especially in CRC. METHODS: We included 15 non-metastatic (low-grade), 11 non-metastatic (high-grade), 10 metastatic colorectal cancer patients and 18 healthy controls. The percentages of CD3+CD56+ NKT cells and NKG2D+CD56+ NKT cells from samples were analyzed by fl ow cytometry in peripheral blood mononuclear cells (PBMCs) of samples. RESULTS: We found that there was a signifi cantly lower number of NKG2D+CD3+CD56+ cells in peripheral blood of patients with metastatic colorectal cancer compared with normal controls (77.53 ± 5.79 % vs 90.74 ± 9.84 %; p<0.01). CONCLUSION: The fact that frequency of NKG2D+CD56+ NKT cells was signifi cantly lower in patients with metastatic colorectal cancer compared to healthy controls strengthens the hypothesis that NKT cells can play a substantial role in the protection against human colorectal cancer, and this opens up avenues for novel studies about elucidating the other aspects of tumor surveillance in CRC progression and immunotherapy (Tab. 2, Fig. 2, Ref. 46). Text in PDF www.elis.sk.

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Beyond Stressed Self: Evidence for NKG2D Ligand Expression on Healthy Cells

Cited by 78 publications

References 117 publications

ULBP6/RAET1L is an additional human NKG2D ligand

ULBP6/RAET1L is an additional human NKG2D ligand

Intracellular Sequestration of the NKG2D Ligand ULBP3 by Human Cytomegalovirus

Decline in peripheral blood NKG2D+CD3+CD56+ NKT cells in metastatic colorectal cancer patients

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