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

Index: Eur. J. Immunol. 44(9) , 2761-70, (2014)

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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 down-modulation 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 MICA-induced 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. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.