c-Cbl regulates MICA-but not ULBP2-induced NKG2D down-modulation in human NK cells

Rosa Molfetta, Linda Quatrini, Cristina Capuano, Francesca Gasparrini, Beatrice Zitti, Alessandra Zingoni, Ricciarda Galandrini, Angela Santoni, Rossella Paolini

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

The NKG2D activating receptor on human NK cells mediates "altered self" recognition, as its ligands (NKG2DLs) are upregulated on target cells in a variety of stress conditions. Evidence collected in the past years shows that, even though expression of NKG2DLs acts as a danger signal that renders tumor cells susceptible to cytotoxicity, chronic exposure to soluble or membrane-bound NKG2DLs can lead to down-modulation of receptor expression and impairment of NKG2D-mediated cell functions. Here, we evaluated whether different cell-bound NKG2DLs, namely MICA and ULBP2, are equivalently able to induce NKG2D down-modulation on human NK cells. We found that although both ligands reduce NKG2D surface expression, MICA promotes a stronger receptor downmodulation than ULBP2, leading to a severe impairment of NKG2D-dependent NK-cell cytotoxicity.We also provide evidence that the ubiquitin pathway and c-Cbl direct MICAinduced but not ULBP2-induced NKG2D internalization and degradation, thus identifying a molecular mechanism to explain the differential effects of MICA and ULBP2 on NKG2D expression. A better understanding of the molecular mechanisms employed by the different NKG2DLs to control NKG2D surface expression could be useful for the development of anti-tumor strategies to restore a normal level of NKG2D receptors on human NK cells.

Original languageEnglish
Pages (from-to)2761-2770
Number of pages10
JournalEuropean Journal of Immunology
Volume44
Issue number9
DOIs
Publication statusPublished - 2014

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Natural Killer Cells
NK Cell Lectin-Like Receptor Subfamily K
Ligands
Ubiquitin
Neoplasms
Membranes

Keywords

  • Endocytosis
  • NK cells
  • NKG2D ligands
  • NKG2D receptor

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Molfetta, R., Quatrini, L., Capuano, C., Gasparrini, F., Zitti, B., Zingoni, A., ... Paolini, R. (2014). c-Cbl regulates MICA-but not ULBP2-induced NKG2D down-modulation in human NK cells. European Journal of Immunology, 44(9), 2761-2770. https://doi.org/10.1002/eji.201444512

c-Cbl regulates MICA-but not ULBP2-induced NKG2D down-modulation in human NK cells. / Molfetta, Rosa; Quatrini, Linda; Capuano, Cristina; Gasparrini, Francesca; Zitti, Beatrice; Zingoni, Alessandra; Galandrini, Ricciarda; Santoni, Angela; Paolini, Rossella.

In: European Journal of Immunology, Vol. 44, No. 9, 2014, p. 2761-2770.

Research output: Contribution to journalArticle

Molfetta, R, Quatrini, L, Capuano, C, Gasparrini, F, Zitti, B, Zingoni, A, Galandrini, R, Santoni, A & Paolini, R 2014, 'c-Cbl regulates MICA-but not ULBP2-induced NKG2D down-modulation in human NK cells', European Journal of Immunology, vol. 44, no. 9, pp. 2761-2770. https://doi.org/10.1002/eji.201444512
Molfetta R, Quatrini L, Capuano C, Gasparrini F, Zitti B, Zingoni A et al. c-Cbl regulates MICA-but not ULBP2-induced NKG2D down-modulation in human NK cells. European Journal of Immunology. 2014;44(9):2761-2770. https://doi.org/10.1002/eji.201444512
Molfetta, Rosa ; Quatrini, Linda ; Capuano, Cristina ; Gasparrini, Francesca ; Zitti, Beatrice ; Zingoni, Alessandra ; Galandrini, Ricciarda ; Santoni, Angela ; Paolini, Rossella. / c-Cbl regulates MICA-but not ULBP2-induced NKG2D down-modulation in human NK cells. In: European Journal of Immunology. 2014 ; Vol. 44, No. 9. pp. 2761-2770.
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