NKG2D engagement on human NK cells leads to DNAM-1 hypo-responsiveness through different converging mechanisms.

Natural killer (NK) cell activation is regulated by activating and inhibitory receptors that facilitate diseased cell recognition. Among activating receptors, NKG2D and DNAM-1 play a pivotal role in anti-cancer immune responses since they bind ligands upregulated on transformed cells. During tumor progression, however, these receptors are frequently down-modulated and rendered functionally inactive. Of note, NKG2D internalization has been associated to the acquisition of a dysfunctional phenotype characterized by the cross-tolerization of unrelated activating receptors. However, our knowledge of the consequences of NKG2D engagement is still incomplete. Here, by cytotoxicity assays combined with confocal microscopy. we demonstrate that NKG2D engagement on human NK cells impairs DNAM-1-mediated killing through two different converging mechanisms: by the upregulation of the checkpoint inhibitory receptor TIGIT, that in turn suppress DNAM-1-mediated cytotoxic function, and by a direct inhibition of DNAM-1-promoted signalling. Our results highlight a novel interplay between NKG2D and DNAM-1/TIGIT receptors that may facilitate neoplastic cells evasion from NK cell-mediated clearance. This article is protected by copyright. All rights reserved.