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      Soluble HLA-I-mediated secretion of TGF-beta1 by human NK cells and consequent down-regulation of anti-tumor cytolytic activity.

      European Journal of Immunology

      secretion, Animals, Tumor Necrosis Factor-alpha, metabolism, genetics, Transforming Growth Factor beta1, Solubility, Reverse Transcriptase Polymerase Chain Reaction, Receptors, KIR2DL2, Receptors, KIR2DL1, Receptors, KIR, RNA, Messenger, Protein Binding, NK Cell Lectin-Like Receptor Subfamily K, immunology, cytology, Killer Cells, Natural, Interferon-gamma, Humans, HLA-C Antigens, HLA Antigens, Flow Cytometry, Down-Regulation, Cytotoxicity, Immunologic, Cell Survival, Cell Proliferation, Cell Line, Tumor, Antigens, CD8

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          Soluble HLA class I (sHLA-I) molecules can regulate survival of NK cells and their anti-tumor killing activity. Herein, we have analysed whether interaction of sHLA-I with CD8 and/or different isoforms of killer Ig-like receptors (KIR) induced secretion of transforming growth factor (TGF)-beta1. CD8+KIR- NK cell clones secreted TGF-beta1 upon the interaction of sHLA-I with CD8 molecule. sHLA-Cw4 or sHLA-Cw3 alleles engaging inhibitory isoforms of KIR, namely KIR2DL1 or KIR2DL2, strongly downregulated TGF-beta1 production elicited through CD8. On the other hand, sHLA-Cw4 or sHLA-Cw3 alleles induced secretion of TGF-beta1 by ligation of stimulatory KIR2DS1 or KIR2DS2 isoforms. TGF-beta1 strongly reduced NK cell-mediated tumor cell lysis and production of pro-inflammatory cytokines such as TNF-alpha and IFN-gamma. Also, TGF-beta1 inhibited NK cell cytolysis induced by the engagement of stimulatory receptors including NKG2D, DNAM1, 2B4, CD69, NKp30, NKp44 and NKp46. The IL-2-dependent surface upregulation of some of these receptors was prevented by TGF-beta1. Furthermore, TGF-beta1 hampered IL-2-induced NK cell proliferation but not IL-2-mediated rescue from apoptosis of NK cells. Depletion of TGF-beta1 restored all the NK cell-mediated functional activities analysed. Taken together these findings suggest that sHLA-I antigens may downregulate the NK cell-mediated innate response by inducing TGF-beta1 release.

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