Editors' ChoiceImmunology

New connections: Manipulating NK cell responses

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Science Signaling  30 May 2017:
Vol. 10, Issue 481, eaan8369
DOI: 10.1126/scisignal.aan8369

Manipulating ligand interactions with the activating receptor NKG2D modulates natural killer cell responses.

Natural killer (NK) cells target virally infected and tumor cells for death through cytolysis. NK cell activation depends on the balance between signals mediated by different combinations of activating and inhibitory receptors. When sufficient numbers of the activating receptor NKG2D are engaged by its ligands, including members of the ULBP family, on the target cell, the NK cell kills the target. ULBP-encoding genes contain polymorphisms that are associated with immune dysfunction. Zuo et al. found that a commonly occurring ULBP6 variant had an affinity for NKG2D that was greater than that of the wild-type protein, which impaired NK cell activation. A soluble form of this protein variant bound so tightly to NKG2D that it suppressed receptor activation and target cell killing in response to other NKG2D ligands. The shedding of soluble NKG2D ligands by tumor cells was thought to lead to immune evasion by desensitizing NK cells and other cytotoxic cells. However, Deng et al. showed that the tumor cell–derived NKG2D ligand MULT1 stimulated tumor rejection in mice. MULT1 appeared to reverse the NK cell desensitization caused by other NKG2D ligands expressed on the tumor cells. Together, these studies suggest that soluble ligands are immunomodulatory and that targeting NK cell–ligand interactions may provide therapies to fine-tune the immune response.

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