TGF-β and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells (original) (raw)

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Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen

Tübingen, Germany

Correspondence to: Günter Eisele, MD, Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Strasse 3, D-72076 Tübingen, Germany E-mail: guenter.eisele@uni-tuebingen.de

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Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen

Tübingen, Germany

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Institute for Brain Research, Department of Immunology, University of Tübingen

Tübingen, Germany

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Institute for Brain Research, Department of Immunology, University of Tübingen

Tübingen, Germany

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Institute for Cell Biology, Department of Immunology, University of Tübingen

Tübingen, Germany

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Institute for Cell Biology, Department of Immunology, University of Tübingen

Tübingen, Germany

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Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen

Tübingen, Germany

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Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen

Tübingen, Germany

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Present address: Weatherall Institute of Molecular Medicine, MRC Human Immunology Unit, John Radcliffe Hospital

Oxford, UK

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Received:

26 January 2006

Revision received:

27 June 2006

Published:

03 August 2006

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Günter Eisele, Jörg Wischhusen, Michel Mittelbronn, Richard Meyermann, Inja Waldhauer, Alexander Steinle, Michael Weller, Manuel A. Friese, TGF-β and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells, Brain, Volume 129, Issue 9, September 2006, Pages 2416–2425, https://doi.org/10.1093/brain/awl205
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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-β (TGF-β) 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-β 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-β 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.

© The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Topic:

• immunosuppressive agents
• brain tumors
• cancer
• glioma
• immunologic surveillance
• ligands
• metalloproteases
• world health organization
• antibodies
• brain
• autocrine
• cytokinesis
• rna, small interfering
• cytolysis
• glioma, malignant
• ulbp3 gene
• molecule
• neoplasm grading

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