Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor<i>in vivo</i>

Cerwenka, Adelheid; Baron, Jody L.; Lanier, Lewis L.

doi:10.1073/pnas.201238598

Cited by 534 publications

(469 citation statements)

References 35 publications

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“…Although normal cells are NKcell-resistant due to MHC class I-mediated NK-cell inhibition, de novo expression of NKG2D-L could also initiate lysis of targets that were MHC class I-positive [16,17]. This suggested that crosslinking of NKG2D was sufficient for rejection of ligand-expressing tumor cell lines.…”

Section: Introductionmentioning

confidence: 99%

Requirements for control of B‐cell lymphoma by NK cells

et al. 2010

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The role of NK cells in the control of endogenously arising tumors is still unclear. We monitored activation and effector functions of NK cells in a c‐myc‐transgenic mouse model of spontaneously arising lymphoma. At early stages, tumors demonstrated reduced MHC class I expression and increased expression of natural killer group 2D ligands (NKG2D‐L). NK cells in these tumors showed an activated phenotype that correlated with the loss of tumor MHC class I. With increasing tumor load however, NK‐cell effector functions became progressively paralyzed or exhausted. In later stages of disease, tumors re‐expressed MHC class I and lost NKG2D‐L, suggesting a role of these two signals for NK cell‐mediated tumor control. Testing a panel of lymphoma cell lines expressing various MHC class I and NKG2D‐L levels suggested that NK cell‐dependent tumor control required a priming and a triggering signal that were provided by MHC class I down‐regulation and by NKG2D‐L, respectively. Deleting either of the “two signals” resulted in tumor escape. At early disease stages, immune stimulation through TLR‐ligands in vivo efficiently delayed lymphoma growth in a strictly NK cell‐dependent manner. Thus, NK‐receptor coengagement is crucial for NK‐cell functions in vivo and especially for NK cell‐mediated tumor surveillance.

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Section: Introductionmentioning

confidence: 99%

Requirements for control of B‐cell lymphoma by NK cells

et al. 2010

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“…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 many viruses have evolved one, and sometimes multiple, mechanisms to prevent cell-surface expression of NKG2D ligand [21].…”

Section: Introductionmentioning

confidence: 99%

ULBP6/RAET1L is an additional human NKG2D ligand

Eagle¹,

Traherne²,

Hair³

et al. 2009

Eur J Immunol

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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“…1,2 Natural or engineered expression of NKG2D ligands (NKG2DLs) on tumor cells greatly enhances their sensitivity to killing by NK cells in vitro, even when the tumor cells express normal levels of MHC class I molecules. 3 However, the shedding of soluble MICA promotes downregulation of NKG2D on NK and CD8 1 T cells due to NKG2D internalization. 4,5 The impact of solid-phase MICA protein on the expansion and function of NK cells remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Immobilized MHC class I chain-related protein A synergizes with IL-15 and soluble 4-1BB ligand to expand NK cells with high cytotoxicity ex vivo

Gong

Xiao

et al. 2010

Cell Mol Immunol

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Major histocompatibility complex (MHC) class I chain-related protein A (MICA), which is a ligand for human NKG2D, is expressed by a variety of epithelial tumor cells and promotes the activation of natural killer (NK), CD8 1 and cd-T cells. Although ectopic expression of MICA on tumor cells elicits anti-tumor responses, soluble MICA downregulates the activities of lymphocytes. In this study, we showed that recombinant, immobilized MICA (iMICA) molecules coated on plastic wells weakly promote peripheral NK cell activation, secretion of interferon (IFN)-c and degranulation without inducing apoptosis. In addition, iMICA synergized with IL-15 and soluble 4-1BB ligand (s4-1BBL) to expand NK cells 25-to 42-fold in a 13-day culture, whereas NK cells stimulated only with IL-15 and s4-1BBL expanded 10-to 16-fold. In contrast to NK cells expanded by IL-15 and s4-1BBL stimulation, NK cells expanded long term in the presence of iMICA exhibited increased cytotoxicity against leukemia cells. These results suggest that large numbers of NK cells with high cytotoxicity can be generated by stimulation with IL-15 and s4-1BBL in the presence of iMICA and that these cells can be used for adoptive cancer immunotherapy. Studies on the 4-1BB signaling pathway have shown that ligation of 4-1BB promotes the survival and multiplication of CD8 1 T and NK cells. 6 IL-15 is essential for the development and function of NK cells. 7 Coculture of NK cells with K562 cells ectopically coexpressing 4-1BB ligand (4-1BBL) and membrane-bound IL-15 effectively promotes the expansion of NK cells in vitro and mediates their cytotoxicity against some leukemia cells. 8,9 In addition, IL-15 upregulates the expression of NKG2D on NK and T cells, even in the presence of soluble NKG2DL. 10 IL-15 and NKG2D signals cross-regulate each other and

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Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumorin vivo

Cited by 534 publications

References 35 publications

Requirements for control of B‐cell lymphoma by NK cells

Requirements for control of B‐cell lymphoma by NK cells

ULBP6/RAET1L is an additional human NKG2D ligand

Immobilized MHC class I chain-related protein A synergizes with IL-15 and soluble 4-1BB ligand to expand NK cells with high cytotoxicity ex vivo

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