Proteolytic release of soluble UL16-binding protein 2 from tumor cells.
The MHC class I-related ligands of the immunoreceptor NKG2D are frequently expressed by tumor cells and stimulate tumor immunity mediated by CD8 T cells and natural killer (NK) cells. In humans, NKG2D ligands (NKG2DL) are encoded by the MHC-encoded MIC and non-MHC-encoded UL16-binding protein (ULBP) families of proteins. Recently, we and others showed that tumor cells release soluble MICA (sMICA), thereby counteracting NKG2D-mediated tumor immunosurveillance. Here, we now report that ULBP2 molecules are likewise released from tumor cells in a processed soluble form, and that soluble ULBP2 (sULBP2) can be detected in sera of some patients with hematopoietic malignancies. Tumor cell-derived sULBP2 as opposed to cell-bound ULBP2 does not down-regulate NKG2D on NK cells. Unexpectedly, the glycosylphosphatidylinositol-anchored ULBP2 molecules are not released by phospholipases but by the action of metalloproteases. Proteolytic shedding of both NKG2D ligands MICA and ULBP2 by tumor cells was strongly enhanced after phorbol 12-myristate 13-acetate treatment and paralleled by a markedly reduced susceptibility to NKG2D-mediated cytotoxicity. Shedding of MICA and ULBP2 can be blocked by the same inhibitors, suggesting the involvement of related metalloproteases. Thus, our data suggest that reducing NKG2DL surface densities is due to a common cleavage process executed by metalloproteases that promotes escape of tumors from NKG2D-mediated immunosurveillance.
Waldhauer
Inja
I
Department of Immunology, Institute for Cell Biology, Eberhard-Karls University Tübingen, Tübingen, Germany.
Steinle
Alexander
A
D002352:Carrier Proteins / Q000097:blood / Q000378:metabolism*; D015536:Down-Regulation; D058851:GPI-Linked Proteins; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D018922:HL-60 Cells; D019337:Hematologic Neoplasms / Q000097:blood / Q000201:enzymology / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000097:blood / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D020014:K562 Cells; D008024:Ligands; D045726:Metalloproteases / Q000378:metabolism*; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D012995:Solubility; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D002352:Carrier Proteins; D058851:GPI-Linked Proteins; D017261:Glycosylphosphatidylinositols; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C423230:ULBP2 protein, human; D045726:Metalloproteases; D013755:Tetradecanoylphorbol Acetate