title: TGF-beta and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells.
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.affiliation: Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. guenter.eisele@uni-tuebingen.de
authors.forename: Günter
authors.initials: G
authors.lastname: Eisele
authors.forename: Jörg
authors.initials: J
authors.lastname: Wischhusen
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Richard
authors.initials: R
authors.lastname: Meyermann
authors.forename: Inja
authors.initials: I
authors.lastname: Waldhauer
authors.forename: Alexander
authors.initials: A
authors.lastname: Steinle
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Friese
mesh_terms: D001932:Brain Neoplasms / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000032:analysis / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000276:immunology; D058851:GPI-Linked Proteins; D005910:Glioma / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000032:analysis / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000276:immunology; D008565:Membrane Proteins / Q000032:analysis / Q000276:immunology; D045726:Metalloproteases / Q000276:immunology* / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic / Q000032:analysis / Q000276:immunology*; D055607:Receptors, Natural Killer Cell; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
chemical_list: D002352:Carrier Proteins; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; C488760:RAET1E protein, human; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D016212:Transforming Growth Factor beta; C423231:ULBP1 protein, human; C423230:ULBP2 protein, human; C423229:ULBP3 protein, human; D045726:Metalloproteases