The activating NKG2D receptor on human NK cells mediates “induced self recognition” in that its ligands are up-regulated by stressed or diseased cells. Evidence collected in the past years demonstrated that chronic exposure to NKG2DLs induces receptor down-modulation. The aim of this study was to evaluate whether different NKG2D ligands (NKG2DLs), namely MICA and ULBP2, are equivalent in their capacities to down-modulate the surface receptor expression on human NK cells. We analyzed the rate and kinetics of NKG2D down-modulation in primary cultured NK cells and in the NKL NK cell line upon stimulation with the Ba/F3 cell line stably overexpressing comparable levels of MICA or ULBP2 by FACS and fluorescence microscopic analysis. Although both ligands were able to reduce NKG2D expression, exposure to MICA over-expressing target cells resulted in a more rapid and efficient receptor down-modulation and in a more pronounced impairment of NKG2D-dependent cytotoxicity. MICA-experienced NK cells also showed a higher tyrosine phosphorylation of the ubiquitin ligase c-Cbl. Furthermore, ligand-induced receptor down-modulation affected the total NKG2D cellular levels, suggesting that the internalized receptor complexes were mainly subjected to degradation. All together these results demonstrate that NKG2D down-regulation is influenced by the nature of its ligand and suggest a different contribution of the ubiquitin pathway in the control of NKG2D internalization and degradation in MICA- versus ULBP2-experienced cells. Understanding the mechanisms of ligand-induced NKG2D down-modulation will be helpful to prevent evasion from NK cell-mediated immune response.

Down-regulation of the NKG2D receptor is differentially controlled by MICA and ULBP2 ligands / Quatrini, Linda; Molfetta, Rosa; Gasparrini, Francesca; Capuano, Cristina; Zingoni, Alessandra; Galandrini, Ricciarda; Santoni, Angela; Paolini, Rossella. - In: FRONTIERS IN IMMUNOLOGY. - ISSN 1664-3224. - ELETTRONICO. - (2013). (Intervento presentato al convegno 15th International Congress Of Immunology tenutosi a Milano, Italia nel 22-27 Agosto, 2013) [10.3389/conf.fimmu.2013.02.00013].

Down-regulation of the NKG2D receptor is differentially controlled by MICA and ULBP2 ligands

QUATRINI, LINDA;MOLFETTA, Rosa;GASPARRINI, FRANCESCA;CAPUANO, CRISTINA;ZINGONI, Alessandra;GALANDRINI, Ricciarda;SANTONI, Angela;PAOLINI, Rossella
2013

Abstract

The activating NKG2D receptor on human NK cells mediates “induced self recognition” in that its ligands are up-regulated by stressed or diseased cells. Evidence collected in the past years demonstrated that chronic exposure to NKG2DLs induces receptor down-modulation. The aim of this study was to evaluate whether different NKG2D ligands (NKG2DLs), namely MICA and ULBP2, are equivalent in their capacities to down-modulate the surface receptor expression on human NK cells. We analyzed the rate and kinetics of NKG2D down-modulation in primary cultured NK cells and in the NKL NK cell line upon stimulation with the Ba/F3 cell line stably overexpressing comparable levels of MICA or ULBP2 by FACS and fluorescence microscopic analysis. Although both ligands were able to reduce NKG2D expression, exposure to MICA over-expressing target cells resulted in a more rapid and efficient receptor down-modulation and in a more pronounced impairment of NKG2D-dependent cytotoxicity. MICA-experienced NK cells also showed a higher tyrosine phosphorylation of the ubiquitin ligase c-Cbl. Furthermore, ligand-induced receptor down-modulation affected the total NKG2D cellular levels, suggesting that the internalized receptor complexes were mainly subjected to degradation. All together these results demonstrate that NKG2D down-regulation is influenced by the nature of its ligand and suggest a different contribution of the ubiquitin pathway in the control of NKG2D internalization and degradation in MICA- versus ULBP2-experienced cells. Understanding the mechanisms of ligand-induced NKG2D down-modulation will be helpful to prevent evasion from NK cell-mediated immune response.
2013
15th International Congress Of Immunology
innate immunity; NK cells; NK receptor; endocytosis; degradation
04 Pubblicazione in atti di convegno::04c Atto di convegno in rivista
Down-regulation of the NKG2D receptor is differentially controlled by MICA and ULBP2 ligands / Quatrini, Linda; Molfetta, Rosa; Gasparrini, Francesca; Capuano, Cristina; Zingoni, Alessandra; Galandrini, Ricciarda; Santoni, Angela; Paolini, Rossella. - In: FRONTIERS IN IMMUNOLOGY. - ISSN 1664-3224. - ELETTRONICO. - (2013). (Intervento presentato al convegno 15th International Congress Of Immunology tenutosi a Milano, Italia nel 22-27 Agosto, 2013) [10.3389/conf.fimmu.2013.02.00013].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/671818
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