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TGF-beta and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells.
Brain. 2006 Sep; 129(Pt 9):2416-25.B

Abstract

NKG2D ligands (NKG2DL) are expressed by infected and transformed cells. They transmit danger signals to NKG2D-expressing immune cells, leading to lysis of NKG2DL-expressing cells. We here report that the NKG2DL MHC class I-chain-related molecules A and B (MICA/B) and UL16-binding proteins (ULBP) 1-3 are expressed in human brain tumours in vivo, while expression levels are low or undetectable in normal brain. MICA and ULBP2 expression decrease with increasing WHO grade of malignancy, while MICB and ULBP1 are expressed independently of tumour grade. We further delineate two independent mechanisms that can explain these expression patterns: (i) transforming growth factor-beta (TGF-beta) is upregulated during malignant progression and selectively downregulates MICA, ULBP2 and ULBP4 expression, while MICB, ULBP1 and ULBP3 are unaffected. (ii) Cleavage of MICA and ULBP2 is reduced by inhibition of metalloproteinases (MP), whereas no changes in the expression levels of other NKG2DL were detected. Consequently, NKG2DL-dependent NK cell-mediated lysis is enhanced by depletion of TGF-beta or inhibition of MP. Thus, escape from NKG2D-mediated immune surveillance of malignant gliomas in vivo may be promoted by the inhibition of MICA and ULBP2 expression via an autocrine TGF-beta loop and by MP-dependent shedding from the cell surface. Loss of MICA and ULBP2, in contrast to other NKG2DL, may be particularly important in glioma immune escape, and differential regulation of human NKG2DL expression is part of the immunosuppressive properties of human malignant glioma cells.

Authors+Show Affiliations

Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. guenter.eisele@uni-tuebingen.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16891318

Citation

Eisele, Günter, et al. "TGF-beta and Metalloproteinases Differentially Suppress NKG2D Ligand Surface Expression On Malignant Glioma Cells." Brain : a Journal of Neurology, vol. 129, no. Pt 9, 2006, pp. 2416-25.
Eisele G, Wischhusen J, Mittelbronn M, et al. TGF-beta and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells. Brain. 2006;129(Pt 9):2416-25.
Eisele, G., Wischhusen, J., Mittelbronn, M., Meyermann, R., Waldhauer, I., Steinle, A., Weller, M., & Friese, M. A. (2006). TGF-beta and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells. Brain : a Journal of Neurology, 129(Pt 9), 2416-25.
Eisele G, et al. TGF-beta and Metalloproteinases Differentially Suppress NKG2D Ligand Surface Expression On Malignant Glioma Cells. Brain. 2006;129(Pt 9):2416-25. PubMed PMID: 16891318.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TGF-beta and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells. AU - Eisele,Günter, AU - Wischhusen,Jörg, AU - Mittelbronn,Michel, AU - Meyermann,Richard, AU - Waldhauer,Inja, AU - Steinle,Alexander, AU - Weller,Michael, AU - Friese,Manuel A, Y1 - 2006/08/03/ PY - 2006/8/8/pubmed PY - 2006/10/5/medline PY - 2006/8/8/entrez SP - 2416 EP - 25 JF - Brain : a journal of neurology JO - Brain VL - 129 IS - Pt 9 N2 - NKG2D ligands (NKG2DL) are expressed by infected and transformed cells. They transmit danger signals to NKG2D-expressing immune cells, leading to lysis of NKG2DL-expressing cells. We here report that the NKG2DL MHC class I-chain-related molecules A and B (MICA/B) and UL16-binding proteins (ULBP) 1-3 are expressed in human brain tumours in vivo, while expression levels are low or undetectable in normal brain. MICA and ULBP2 expression decrease with increasing WHO grade of malignancy, while MICB and ULBP1 are expressed independently of tumour grade. We further delineate two independent mechanisms that can explain these expression patterns: (i) transforming growth factor-beta (TGF-beta) is upregulated during malignant progression and selectively downregulates MICA, ULBP2 and ULBP4 expression, while MICB, ULBP1 and ULBP3 are unaffected. (ii) Cleavage of MICA and ULBP2 is reduced by inhibition of metalloproteinases (MP), whereas no changes in the expression levels of other NKG2DL were detected. Consequently, NKG2DL-dependent NK cell-mediated lysis is enhanced by depletion of TGF-beta or inhibition of MP. Thus, escape from NKG2D-mediated immune surveillance of malignant gliomas in vivo may be promoted by the inhibition of MICA and ULBP2 expression via an autocrine TGF-beta loop and by MP-dependent shedding from the cell surface. Loss of MICA and ULBP2, in contrast to other NKG2DL, may be particularly important in glioma immune escape, and differential regulation of human NKG2DL expression is part of the immunosuppressive properties of human malignant glioma cells. SN - 1460-2156 UR - https://www.unboundmedicine.com/medline/citation/16891318/TGF_beta_and_metalloproteinases_differentially_suppress_NKG2D_ligand_surface_expression_on_malignant_glioma_cells_ L2 - https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awl205 DB - PRIME DP - Unbound Medicine ER -