Research ArticleImmunology

A disease-linked ULBP6 polymorphism inhibits NKG2D-mediated target cell killing by enhancing the stability of NKG2D ligand binding

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Sci. Signal.  30 May 2017:
Vol. 10, Issue 481, eaai8904
DOI: 10.1126/scisignal.aai8904

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Distracting natural killer cells

Natural killer (NK) cells target virally infected and transformed cells for cytolysis. When sufficient activating receptors on the NK cell surface, such as NKG2D, are engaged by ligands on the target cell, such as ULBP proteins, the NK cell kills the target. Polymorphisms within ULBP-encoding genes are associated with immune dysfunction. Zuo et al. found that the affinity of a commonly occurring ULBP6 variant for NKG2D 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. Together, these data suggest that targeting NK cell–ligand interactions may provide therapies to modulate the strength of immune responses.