Brain Advance Access originally published online on August 3, 2006
Brain 2006 129(9):2416-2425; doi:10.1093/brain/awl205
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TGF-ß and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells
1 Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen Tübingen, Germany 2 Institute for Brain Research, Department of Immunology, University of Tübingen Tübingen, Germany 3 Institute for Cell Biology, Department of Immunology, University of Tübingen Tübingen, Germany 4 Present address: Weatherall Institute of Molecular Medicine, MRC Human Immunology Unit, John Radcliffe Hospital Oxford, UK
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{at}uni-tuebingen.de
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-ß (TGF-ß) 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-ß 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-ß 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.
Key Words: glioma; metalloproteinases; NK cells; NKG2DL; TGF-ß
Abbreviations: ADAM, a disintegrin and metalloproteinase; ADAM-TS, ADAM with thrombospondin; E : T, effector : target; (s)MICA/B, (soluble) MHC class I-chain-related molecule A/B; MMP, matrix metalloproteinases; MP, metalloproteinases; NKG2DL, NKG2D ligands; TGF-ß, transforming growth factor-ß; sMICA, soluble MICA; sULBP, soluble UL16-binding protein(s)
Received January 26, 2006. Revised June 27, 2006. Accepted July 5, 2006.
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