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Cutting Edge |
* Department of Internal Medicine II, University Hospital and
Department of Immunology, Eberhard-Karls-University, Tubingen, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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1 T cells in tumor
tissue. We report that human tumor cells spontaneously release a
soluble form of MICA encompassing the three extracellular domains,
which is present at high levels in sera of patients with
gastrointestinal malignancies, but not in healthy donors. Release of
MICA from tumor cells is blocked by inhibition of metalloproteinases,
concomitantly causing accumulation of MICA on the cell surface.
Shedding of MICA by tumor cells may modulate NKG2D-mediated tumor
immune surveillance. In addition, determination of soluble MICA levels
may be implemented as an immunological diagnostic marker in patients
with epithelial malignancies. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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T cells
(3).
Among its ligands is the MHC class I-related, stress-inducible surface
glycoprotein MICA2
that exhibits a highly restricted expression in vivo
(4, 5, 6). Interestingly, MICA is broadly expressed on
epithelial tumors and is associated with increased frequencies of
tumor-infiltrating V1 
T cells (7). Engagement of
NKG2D by MICA expressed on transfectants and tumor cell lines triggers
NK cells and V1 T cells and costimulates CD8 T cells
(4, 8, 9). The structure of MICA is similar to the protein
fold of MHC class I, with an 12 platform domain and a
membrane-proximal Ig-like 3 domain (5). MICA and its
close relative MICB, which also serves as a ligand for NKG2D,
are both polymorphic (10) and the polymorphism has been
shown to affect the affinity for NKG2D (11). More
recently, the UL16-binding proteins (ULBP) have been identified as
additional ligands of NKG2D (11, 12). Their expression in
vivo has yet to be explored.
In the mouse, which lacks MHC class I chain (MIC) genes, a family of
proteins structurally related to ULBP, the retinoic acid-early (RAE-1)
molecules function as ligands for NKG2D (13, 14). RAE-1
expression has been shown to be induced by carcinogens and to stimulate
antitumor activities of T cells (15). Furthermore,
in mice RAE-1-transduced cell lines were eliminated in vivo due to NK
and CD8 T cell activity and induced tumor immunity against the parental
cell line, supporting a role for NKG2D in the tumor immune surveillance
(16, 17).
Several membrane-bound molecules among other protein families such as the Ig-like and the TNF superfamily have been shown to be released as a soluble form. Release of the molecules affects cell-cell interactions by reduction of ligand densities and distally modulates effector cells bearing the respective receptor (18, 19, 20). In this study, we describe that MICA is released as a soluble form from the cell surface of tumor cells and can be detected at high levels in sera of patients with gastrointestinal malignancies.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The cell lines HeLa, HCT116, HT29, LX1, PC3, and SKBR3 were cultured in 10% FCS-IMDM. C1R cells were cultured in 10% FCS-RPMI 1640 and C1R-transfectants in 10% FCS-RPMI 1640 with 1.8 mg G418/ml (PAA Laboratories, Linz, Austria). For the production of soluble MICA-containing culture supernatants, cells were grown in IMDM without any additives for 48 h.
Reagents
Anti-mouse IgG2a-HRP was from purchased Southern Biotechnology Associates (Birmingham, AL). The goat anti-mouse FITC conjugate and the goat anti-mouse HRP conjugate were obtained from Jackson ImmunoResearch (West Grove, PA). N-glycanase was obtained from New England Biolabs (Beverly, MA). For inhibition of metalloproteinases, (N-4-hydroxy-N-1-[(1S)-2-(methylamino)-2-oxo-1-(phenylmethyl) ethyl]-2-(2-methylpropyl)-(2R)-butanediamide) was prepared and used as described previously (21). Pefabloc SC (4-(2-aminoethyl)-benzenesulfonyl fluoride hydrochloride) was purchased from Roche (Mannheim, Germany).
MICA transfectants
The human B cell line C1R and the mouse mastocytoma cell line P815 were stably transfected with full-length cDNA encoding MICA*01, MICA*04, and MICB*01 in RSV.5 neo by electroporation or with Fugene 6 (Roche), respectively, according to standard protocols. The MIC cDNAs have been described previously (8). Transfectants obtained after G418 selection were sorted using a Vantage cytometer (BD Biosciences, Mountain View, CA), if necessary.
Production of soluble MICA*04 in Escherichia coli
Soluble MICA was produced and purified as previously described
(11). In brief, the cDNA encoding the MICA*04 ectodomain
(Glu1 through Lys276) in pET20b (Novagen, Madison, WI) was introduced
in E. coli and MICA*04 production was induced by addition of
isopropyl -D-thiogalactoside. Inclusion
bodies were solubilized and successively dialyzed against decreasing
concentrations of urea. Refolded MICA*04 was purified by gel
filtration, dialyzed against PNEA (50 mM PIPES, pH 7.0, 0.15 M NaCl, 1
mM EDTA, and 0.02% NaN3), and eventually
examined by SDS-PAGE and immunoblotting.
Monoclonal Abs
MIC-specific mAb were raised by immunizing BALB/c mice repeatedly with a mixture of P815-MICA*01, P815-MICA*04, and P815-MICB*01 transfectants according to standard procedures. Hybridoma supernatants were screened by flow cytometry using MICA-transfected C1R cells and hybridoma producing C1R-MICA-specific Abs were subcloned twice. Abs were purified by affinity chromatography on a protein A-Sepharose column. The two mAb clones AMO-1 and BAMO-1 were of isotype IgG1, mAb BAMO-3 was IgG2a.
Flow cytometry
Cells were incubated with the anti-MICA mAb or mouse IgG1 at 10 µg/ml and then, after washing, with goat anti-mouse FITC conjugate (1:100) as secondary reagent. Cells were counterstained with propidium iodide for dead cell exclusion. Samples were analyzed on a FACScan (BD Biosciences).
ELISA
For the detection of soluble MICA (sMICA), two anti-MICA mAb binding to different MICA domains were implemented. Plates were coated with the capture anti-MICA mAb AMO-1 at 2 µg/ml in PBS, then blocked by addition of 100 µl of 15% BSA for 2 h at 37°C and washed. Afterward the standard (recombinant MICA*04 in 7.5% BSA-PBS) and the samples were added and the plates were incubated for 2 h at 37°C. For analysis of patient samples, sera were diluted 1:10 in 5% BSA prior to addition to the plates. After incubation, plates were washed and the detection mAb BAMO-3 at 5 µg/ml in 7.5% BSA-PBS was added for 2 h at 37°C. Plates were then washed and anti-mouse IgG2a-HRP (1:8000 in 7.5% BSA-PBS) was added for 1 h at 37°C. Plates were then washed and developed using the Tetramethylbenzidine Peroxidase Substrate System (KPL, Gaithersburg, MD). The absorbance was measured at 450 nm. Results are shown as means with SD of triplicates.
Immunoblot analysis
Cell supernatants were concentrated 
10-fold and separated on
12% SDS-PAGE gels. Where indicated, samples had been treated before
separation with peptide:N-Glycanase F (PNGaseF) for 1 h
at 37°C according to the manufacturer’s instructions (New England
Biolabs). Gels were blotted to Hybond-ECL membranes (Amersham, Little
Chalfont, U.K.), blocked with PBS containing 10% nonfat dried milk and
5% BSA, and then analyzed with 1 µg/ml anti-MICA mAb BAMO-1.
Binding of BAMO-1 was detected with an HRP-labeled goat anti-mouse
HRP conjugate and chemiluminescence reagent (NEN Life Science Products,
Boston, MA).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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3
domain due to its binding to ULBP212 MICA3 hybrid
molecules expressed on transfected COS cells. Conversely, no binding
was seen for BAMO-1 and AMO-1, and competition with soluble NKG2D for
binding to C1R-MICA*01 cells suggested that their epitopes localize to
the 12 domain (data not shown). The anti-MICA mAb AMO-1
and the anti-MICA/B-specific mAb BAMO-3 were implemented to
establish a highly sensitive sandwich ELISA for sMICA. Recombinant
sMICA*04 was used as a standard and detected at concentrations below
100 pg/ml (Fig. 1
A). Only
background signals were obtained with control proteins (BSA and HLA-A2
tetramer, respectively) at 0.1 µg/ml.
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B and
data not shown). In contrast, supernatants of mock-transfected C1R
cells that constitutively express MICA at low levels (data not shown)
contained much less sMICA (0.5 ng/ml). Since many epithelial tumor
cell lines have been reported to express MICA at various levels on the
cell surface (6, 7, 8), we analyzed supernatants of the
carcinoma cell lines HCT116 (colon), HeLa (cervix), HT29 (colon), SKBR3
(mamma), LX1 (lung), and PC3 (prostate) for sMICA. Except for SKBR3, we
detected significant levels of sMICA in the supernatants of all cell
lines ranging from 0.4 to 3.5 ng/ml (Fig. 1B).
To characterize the molecular nature of sMICA, concentrated
supernatants of C1R transfectants and HCT116 were subjected to
immunoblot analysis. In C1R-MICA*04 supernatants, a smear in the range
between 50 and 60 kDa was detected (Fig. 1C). Accordingly,
in a previous report, membrane-bound MICA immunoprecipitated from C1R
transfectants resulted in diffuse signals that had been attributed to
heavy glycosylation of MICA, which has eight potential
N-linked glycosylation sites in its three extracellular
domains (6). After PNGaseF treatment of C1R-MICA*04
supernatants, two distinct sMICA species, centered around the size of
recombinant sMICA*04 (33 kDa), could be detected, suggesting that
processing may be complex, involving one or more sheddases. Similar
results were obtained with supernatants of C1R-MICA*01 transfectants
(data not shown). Similarly, when supernatants of C1R-neo cells were
investigated after PNGaseF treatment, we detected a weak signal 33
kDa (Fig. 1C). With HCT116 supernatants, a smear similar to
C1R-MICA*04 supernatants was detected, which, after deglycosylation,
changed into a distinct band of 33 kDa (Fig. 1C). Taken
together, these results demonstrate that MICA is spontaneously released
as a soluble, heavy glycosylated form from tumor cell lines expressing
endogenous or transfected MICA. Since 1) the size of the released
protein corresponds to the size of the three extracellular domains of
MICA (i.e., the size of recombinant MICA*04), 2) it is released from
MICA cDNA-transfected cells as well as from cells constitutively
expressing MICA, and 3) because it is detected by mAb that recognize
the 1/2 and 3 domains, respectively, we conclude that sMICA
encompasses the entire MICA ectodomain.
Since it has been shown for various proteins that their membrane-bound
form is cleaved by proteases and released as a soluble form, we
investigated whether there is a similar mechanism for the release of
MICA. C1R-MICA*04, HeLa, and HCT116 were cultured for 24 h in the
presence of a broad serine protease inhibitor (Pefabloc) and a
metalloproteinase inhibitor (matrix metalloproteinase inhibitor
(MMPI)). Subsequently we investigated the levels of sMICA in the
culture supernatants detectable by ELISA. The levels of sMICA were
compared using Student’s t test; results with a
p value below 0.05 were considered to be statistically
significant. In the absence of any compound, supernatants of
MICA*04-transfected C1R cells contained 30 ng/ml sMICA. Addition of
the Pefabloc serine protease inhibitor did not result in significant
changes of detectable levels of sMICA, whereas treatment of cells with
MMPI markedly reduced the release of sMICA. A concentration of 0.5 µM
MMPI in the culture medium caused a statistically significant reduction
of sMICA in the C1R-MICA*04 culture medium (Fig. 2A). With HeLa and HCT116
cells, respectively (Fig. 2, B and C), the levels
of spontaneously released sMICA in the culture medium were lower (2.5
and 7.3 ng/ml, respectively) compared with those seen with the
C1R-MICA*04 transfectants. Again, the addition of the serine protease
inhibitor did not cause relevant changes of sMICA levels, whereas
addition of MMPI concentration-dependently reduced the levels of sMICA
in the cell supernatants. With both HeLa and HCT116 cells,
concentrations of 1 µM MMPI or more caused a statistically
significant reduction of the levels of sMICA. Similar effects of the
MMPI were observed after 48 h of incubation. Treatment with both
protease inhibitors had no effect on tumor cell growth or viability,
thus the reduction in the levels of released sMICA observed with the
MMPI was due to the inhibition of sheddases and not due to a toxic
effect of the compounds (data not shown).
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T cells and stimulated tumor
immunity against the parental cell lines in a mouse model (16, 22). It was shown that the immune response observed in these
studies was critically dependent on the expression levels of NKG2DL on
the tumor cells. Therefore, reduction of MICA expression by release
from the cell surface would potentially reduce immunogenicity of tumor
cells. To investigate whether the effect of sheddases on MICA surface
expression mirrored the changes in the levels of sMICA in the
culture supernatants, C1R-MICA*04 cells, HCT116 cells, and HeLa cells
were cultured in fresh culture medium for 24 h in the presence of
protease inhibitors. MICA surface levels of treated and untreated cells
were determined by FACS using the MICA-specific mAb AMO-1. While
inhibition of serine proteases did not result in significant changes of
MICA surface expression on C1R-MICA*04 transfectants, addition of MMPI
to the culture medium increased levels of membrane-bound MICA in a
concentration-dependent manner (1.5-fold increase in mean
fluorescence; Fig. 2D). The cell lines HeLa and HCT116
showed lower levels of constitutive cell surface MICA expression (Fig. 2D), which also were increased by addition of MMPI to the
culture medium (2- and 3-fold, respectively), but not by Pefabloc.
The MMPI used in these experiments has been reported previously
(21) to inhibit a sheddase-like activity. Matrix
metalloproteinases (MMP) are structurally related endopeptidases
capable of degrading extracellular matrix and are involved in tissue
morphogenesis, repair, and angiogenesis, but have also been shown to
play an important role in the pathophysiology of tumors. Direct
evidence for the involvement of MMP in tumor growth has been provided
by several studies and especially in cancers of the gastrointestinal
tract high levels of MMP are related to poor survival (for review, see
Ref. 23). Degradation of stromal extracellular matrix and
basement membranes due to activity of MMP is believed to contribute to
tumor angiogenesis and invasion capacity in vivo. (23).
There is also accumulating evidence for immunomodulatory functions of
MMP. For example, TNF mediates systemic functions following shedding
from the cell surface due to the activity of MMP (18),
while MMP-mediated conversion of membrane-bound Fas ligand (CD178) to
its soluble form has been shown to be associated with down-regulation
of its proapoptotic activity (19). In the case of MICA,
reduction of surface expression on tumor cells by MMP lowers the levels
of NKG2DL capable of inducing a cellular antitumor response by
cytotoxic lymphocytes and may provide a mechanism for the cells to
escape local immune surveillance by limiting activating signals to the
host. In fact, it has been shown that expression levels of NKG2DL on
the surface of target cells critically determine the outcome of
NKG2D-mediated immune responses. Cell stress-induced increase of MICA
expression on tumor cells renders these more susceptible to lysis by
V1 T cells (8), and an enhanced NKG2DL expression
triggers NK cells overcoming inhibitory signals by MHC class I
molecules (4, 12). Furthermore, it has been shown that
there is a clear correlation of NKG2DL surface levels on
NKG2DL-transduced tumor cell lines with regard to their capacity to
stimulate tumor immunity in vivo (16).
To investigate the role of shedding of MICA as a potential immune
escape mechanism of human tumors in vivo, we analyzed sMICA levels in
sera of patients with gastrointestinal malignancies. Serum samples of
healthy volunteers and patients were collected and assayed by ELISA for
sMICA. All investigated sera of healthy volunteers contained low levels
of sMICA ranging between 0.6 and 1.0 ng/ml, with mean and median values
of 0.8 and 0.8 ng/ml, respectively, which is close to the detection
limit of the ELISA (Fig. 3). Sera from
patients with stomach carcinoma showed levels of sMICA ranging between
1.9 and 11.3 ng/ml, with a mean of 5.5 ng/ml and a median of 5.1 ng/ml.
In patients with colon carcinoma, the range of sMICA was between 2.0
and 7.9 ng/ml, the mean being 5.5 ng/ml and the median 5.9 ng/ml. The
highest levels of sMICA were detected in sera from patients with rectum
carcinoma; the range was between 1.6 and 17.1 ng/ml, with a mean of 6.5
ng/ml and a median of 5.4 ng/ml. The presence of sMICA in patient sera
was validated by immunoblot analysis of sera following PNGaseF
treatment, which revealed a band comparable to that of sMICA in culture
supernatants (data not shown). The differences of the levels of sMICA
in sera of healthy donors and patients with stomach carcinoma, colon
carcinoma, and rectal carcinoma were statistically significant
(p < 0.001) as determined by Student’s
t test. This strong correlation of tumor incidence and
elevated sMICA levels clearly suggests that MICA is released at
significant amounts from tumor cells in vivo. Elevated levels were
detected in all patient sera regardless of presumed allelic MICA
differences. The impact of cleavage of membrane-bound MICA to its
soluble form on cell-cell interactions and the effect of sMICA at
distal sites, which might account for some of the pathophysiology of
malignant diseases, require further elucidation.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: MICA, MHC class I chain-related gene A; MICB, MIC gene B; ULBP, UL16-binding protein; RAE-1, retinoic acid early inducible gene 1; sMICA, soluble MICA; PNGase F, peptide:N-glycanase F; MMPI, matrix metalloproteinase inhibitor; MMP, matrix metalloproteinase.
Received for publication July 16, 2002. Accepted for publication August 22, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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T cells. Science 279:1737. T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat. Immunol. 2:255.[Medline]
T cells. Science 294:605. processing by a metalloproteinase inhibitor. Nature 370:558.[Medline]
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M. Jinushi, M. Vanneman, N. C. Munshi, Y.-T. Tai, R. H. Prabhala, J. Ritz, D. Neuberg, K. C. Anderson, D. R. Carrasco, and G. Dranoff MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma PNAS, January 29, 2008; 105(4): 1285 - 1290. [Abstract] [Full Text] [PDF]
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L. Andresen, H. Jensen, M. T. Pedersen, K. A. Hansen, and S. Skov Molecular Regulation of MHC Class I Chain-Related Protein A Expression after HDAC-Inhibitor Treatment of Jurkat T Cells J. Immunol., December 15, 2007; 179(12): 8235 - 8242. [Abstract] [Full Text] [PDF]
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 J. R. Ostberg, B. E. Dayanc, M. Yuan, E. Oflazoglu, and E. A. Repasky Enhancement of natural killer (NK) cell cytotoxicity by fever-range thermal stress is dependent on NKG2D function and is associated with plasma membrane NKG2D clustering and increased expression of MICA on target cells J. Leukoc. Biol., November 1, 2007; 82(5): 1322 - 1331. [Abstract] [Full Text] [PDF]
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W. Cao, X. Xi, Z. Hao, W. Li, Y. Kong, L. Cui, C. Ma, D. Ba, and W. He RAET1E2, a Soluble Isoform of the UL16-binding Protein RAET1E Produced by Tumor Cells, Inhibits NKG2D-mediated NK Cytotoxicity J. Biol. Chem., June 29, 2007; 282(26): 18922 - 18928. [Abstract] [Full Text] [PDF]
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 P. Roda-Navarro and H. T. Reyburn Intercellular protein transfer at the NK cell immune synapse: mechanisms and physiological significance FASEB J, June 1, 2007; 21(8): 1636 - 1646. [Abstract] [Full Text] [PDF]
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P. K. Epling-Burnette, F. Bai, J. S. Painter, D. E. Rollison, H. R. Salih, M. Krusch, J. Zou, E. Ku, B. Zhong, D. Boulware, et al. Reduced natural killer (NK) function associated with high-risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors Blood, June 1, 2007; 109(11): 4816 - 4824. [Abstract] [Full Text] [PDF]
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A. Barber, T. Zhang, L. R. DeMars, J. Conejo-Garcia, K. F. Roby, and C. L. Sentman Chimeric NKG2D Receptor-Bearing T Cells as Immunotherapy for Ovarian Cancer Cancer Res., May 15, 2007; 67(10): 5003 - 5008. [Abstract] [Full Text] [PDF]
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J. Giustiniani, A. Marie-Cardine, and A. Bensussan A Soluble Form of the MHC Class I-Specific CD160 Receptor Is Released from Human Activated NK Lymphocytes and Inhibits Cell-Mediated Cytotoxicity J. Immunol., February 1, 2007; 178(3): 1293 - 1300. [Abstract] [Full Text] [PDF]
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T. Osaki, H. Saito, T. Yoshikawa, S. Matsumoto, S. Tatebe, S. Tsujitani, and M. Ikeguchi Decreased NKG2D Expression on CD8+ T Cell Is Involved in Immune Evasion in Patients with Gastric Cancer Clin. Cancer Res., January 15, 2007; 13(2): 382 - 387. [Abstract] [Full Text] [PDF]
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 K. Tosh, M. Ravikumar, J. T. Bell, S. Meisner, A. V.S. Hill, and R. Pitchappan Variation in MICA and MICB genes and enhanced susceptibility to paucibacillary leprosy in South India Hum. Mol. Genet., October 1, 2006; 15(19): 2880 - 2887. [Abstract] [Full Text] [PDF]
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J. Spreu, T. Stehle, and A. Steinle Human Cytomegalovirus-Encoded UL16 Discriminates MIC Molecules by Their {alpha}2 Domains. J. Immunol., September 1, 2006; 177(5): 3143 - 3149. [Abstract] [Full Text] [PDF]
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 G. Eisele, J. Wischhusen, M. Mittelbronn, R. Meyermann, I. Waldhauer, A. Steinle, M. Weller, and M. A. Friese TGF-{beta} and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells Brain, September 1, 2006; 129(9): 2416 - 2425. [Abstract] [Full Text] [PDF]
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C. L. Sutherland, B. Rabinovich, N. J. Chalupny, P. Brawand, R. Miller, and D. Cosman ULBPs, human ligands of the NKG2D receptor, stimulate tumor immunity with enhancement by IL-15 Blood, August 15, 2006; 108(4): 1313 - 1319. [Abstract] [Full Text] [PDF]
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M. Jinushi, F. S. Hodi, and G. Dranoff Therapy-induced antibodies to MHC class I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity PNAS, June 13, 2006; 103(24): 9190 - 9195. [Abstract] [Full Text] [PDF]
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T. Zhang, A. Barber, and C. L. Sentman Generation of Antitumor Responses by Genetic Modification of Primary Human T Cells with a Chimeric NKG2D Receptor Cancer Res., June 1, 2006; 66(11): 5927 - 5933. [Abstract] [Full Text] [PDF]
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S. Gasser and D. H. Raulet The DNA damage response arouses the immune system. Cancer Res., April 15, 2006; 66(8): 3959 - 3962. [Abstract] [Full Text] [PDF]
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N. Boissel, D. Rea, V. Tieng, N. Dulphy, M. Brun, J.-M. Cayuela, P. Rousselot, R. Tamouza, P. Le Bouteiller, F.-X. Mahon, et al. BCR/ABL oncogene directly controls MHC class I chain-related molecule A expression in chronic myelogenous leukemia. J. Immunol., April 15, 2006; 176(8): 5108 - 5116. [Abstract] [Full Text] [PDF]
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L. Mincheva-Nilsson, O. Nagaeva, T. Chen, U. Stendahl, J. Antsiferova, I. Mogren, J. Hernestal, and V. Baranov Placenta-Derived Soluble MHC Class I Chain-Related Molecules Down-Regulate NKG2D Receptor on Peripheral Blood Mononuclear Cells during Human Pregnancy: A Possible Novel Immune Escape Mechanism for Fetal Survival J. Immunol., March 15, 2006; 176(6): 3585 - 3592. [Abstract] [Full Text] [PDF]
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I. Waldhauer and A. Steinle Proteolytic Release of Soluble UL16-Binding Protein 2 from Tumor Cells. Cancer Res., March 1, 2006; 66(5): 2520 - 2526. [Abstract] [Full Text] [PDF]
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E. P. von Strandmann, H. P. Hansen, K. S. Reiners, R. Schnell, P. Borchmann, S. Merkert, V. R. Simhadri, A. Draube, M. Reiser, I. Purr, et al. A novel bispecific protein (ULBP2-BB4) targeting the NKG2D receptor on natural killer (NK) cells and CD138 activates NK cells and has potent antitumor activity against human multiple myeloma in vitro and in vivo Blood, March 1, 2006; 107(5): 1955 - 1962. [Abstract] [Full Text] [PDF]
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S. Skov, M. T. Pedersen, L. Andresen, P. Thor Straten, A. Woetmann, and N. Odum Cancer Cells Become Susceptible to Natural Killer Cell Killing after Exposure to Histone Deacetylase Inhibitors Due to Glycogen Synthase Kinase-3-Dependent Expression of MHC Class I-Related Chain A and B Cancer Res., December 1, 2005; 65(23): 11136 - 11145. [Abstract] [Full Text] [PDF]
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A. Poggi, C. Prevosto, A.-M. Massaro, S. Negrini, S. Urbani, I. Pierri, R. Saccardi, M. Gobbi, and M. R. Zocchi Interaction between Human NK Cells and Bone Marrow Stromal Cells Induces NK Cell Triggering: Role of NKp30 and NKG2D Receptors J. Immunol., November 15, 2005; 175(10): 6352 - 6360. [Abstract] [Full Text] [PDF]
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C. Germain, C. Larbouret, V. Cesson, A. Donda, W. Held, J.-P. Mach, A. Pelegrin, and B. Robert MHC Class I-Related Chain A Conjugated to Antitumor Antibodies Can Sensitize Tumor Cells to Specific Lysis by Natural Killer Cells Clin. Cancer Res., October 15, 2005; 11(20): 7516 - 7522. [Abstract] [Full Text] [PDF]
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A. K. Kriegeskorte, F. E. Gebhardt, S. Porcellini, M. Schiemann, C. Stemberger, T. J. Franz, K. M. Huster, L. N. Carayannopoulos, W. M. Yokoyama, M. Colonna, et al. NKG2D-independent suppression of T cell proliferation by H60 and MICA PNAS, August 16, 2005; 102(33): 11805 - 11810. [Abstract] [Full Text] [PDF]
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S. Armeanu, M. Bitzer, U. M. Lauer, S. Venturelli, A. Pathil, M. Krusch, S. Kaiser, J. Jobst, I. Smirnow, A. Wagner, et al. Natural Killer Cell-Mediated Lysis of Hepatoma Cells via Specific Induction of NKG2D Ligands by the Histone Deacetylase Inhibitor Sodium Valproate Cancer Res., July 15, 2005; 65(14): 6321 - 6329. [Abstract] [Full Text] [PDF]
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K. Wiemann, H.-W. Mittrucker, U. Feger, S. A. Welte, W. M. Yokoyama, T. Spies, H.-G. Rammensee, and A. Steinle Systemic NKG2D Down-Regulation Impairs NK and CD8 T Cell Responses In Vivo J. Immunol., July 15, 2005; 175(2): 720 - 729. [Abstract] [Full Text] [PDF]
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D. Garrity, M. E. Call, J. Feng, and K. W. Wucherpfennig The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure PNAS, May 24, 2005; 102(21): 7641 - 7646. [Abstract] [Full Text] [PDF]
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P. Nowbakht, M.-C. S. Ionescu, A. Rohner, C. P. Kalberer, E. Rossy, L. Mori, D. Cosman, G. De Libero, and A. Wodnar-Filipowicz Ligands for natural killer cell-activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias Blood, May 1, 2005; 105(9): 3615 - 3622. [Abstract] [Full Text] [PDF]
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Y. Zou, W. Bresnahan, R. T. Taylor, and P. Stastny Effect of Human Cytomegalovirus on Expression of MHC Class I-Related Chains A J. Immunol., March 1, 2005; 174(5): 3098 - 3104. [Abstract] [Full Text] [PDF]
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A. Poggi, C. Venturino, S. Catellani, M. Clavio, M. Miglino, M. Gobbi, A. Steinle, P. Ghia, S. Stella, F. Caligaris-Cappio, et al. V{delta}1 T Lymphocytes from B-CLL Patients Recognize ULBP3 Expressed on Leukemic B Cells and Up-Regulated by Trans-Retinoic Acid Cancer Res., December 15, 2004; 64(24): 9172 - 9179. [Abstract] [Full Text] [PDF]
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 H. R. Salih, P. Stieber, A. Peterfi, D. Nagel, L. Kanz, A. L. Steinle, and S. Holdenrieder Determination of Soluble MICA in Serum as a Novel Marker for Tumor Stage and Metastasis. Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 1344 - 1344. [Abstract]
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L. Bacon, R. A. Eagle, M. Meyer, N. Easom, N. T. Young, and J. Trowsdale Two Human ULBP/RAET1 Molecules with Transmembrane Regions Are Ligands for NKG2D J. Immunol., July 15, 2004; 173(2): 1078 - 1084. [Abstract] [Full Text] [PDF]
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J.-C. Lee, K.-M. Lee, D.-W. Kim, and D. S. Heo Elevated TGF-{beta}1 Secretion and Down-Modulation of NKG2D Underlies Impaired NK Cytotoxicity in Cancer Patients J. Immunol., June 15, 2004; 172(12): 7335 - 7340. [Abstract] [Full Text] [PDF]
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G. Ferlazzo and C. Munz NK Cell Compartments and Their Activation by Dendritic Cells J. Immunol., February 1, 2004; 172(3): 1333 - 1339. [Full Text] [PDF]
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E. S. Doubrovina, M. M. Doubrovin, E. Vider, R. B. Sisson, R. J. O'Reilly, B. Dupont, and Y. M. Vyas Evasion from NK Cell Immunity by MHC Class I Chain-Related Molecules Expressing Colon Adenocarcinoma J. Immunol., December 15, 2003; 171(12): 6891 - 6899. [Abstract] [Full Text] [PDF]
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S. Hue, R. C. Monteiro, S. Berrih-Aknin, and S. Caillat-Zucman Potential Role of NKG2D/MHC Class I-Related Chain A Interaction in Intrathymic Maturation of Single-Positive CD8 T Cells J. Immunol., August 15, 2003; 171(4): 1909 - 1917. [Abstract] [Full Text] [PDF]
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H. R. Salih, H. Antropius, F. Gieseke, S. Z. Lutz, L. Kanz, H.-G. Rammensee, and A. Steinle Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia Blood, August 15, 2003; 102(4): 1389 - 1396. [Abstract] [Full Text] [PDF]
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V. Groh, A. Bruhl, H. El-Gabalawy, J. L. Nelson, and T. Spies Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis PNAS, August 5, 2003; 100(16): 9452 - 9457. [Abstract] [Full Text] [PDF]
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C. Dunn, N. J. Chalupny, C. L. Sutherland, S. Dosch, P.V. Sivakumar, D. C. Johnson, and D. Cosman Human Cytomegalovirus Glycoprotein UL16 Causes Intracellular Sequestration of NKG2D Ligands, Protecting Against Natural Killer Cell Cytotoxicity J. Exp. Med., June 2, 2003; 197(11): 1427 - 1439. [Abstract] [Full Text] [PDF]
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