NKG2D is an activating receptor on NK cells that recognizes a variety of ligands and is involved in the immune response to tumors. In Science, Raulet and colleagues investigate the role of a secreted form of the NKG2D ligand MULT1 in tumor rejection. Tumors secrete such NKG2D ligands, and generally these are thought to antagonize the activation of NK cells. Here, however, the authors find that secreted MULT1 improves the recognition and destruction of implanted tumors by NK cells. Normally, the interaction of NKG2D with membrane-bound ligands found on cells in the tumor microenvironment results in downregulation of NKG2D and desensitization of NK cells. However, in the presence of high-affinity monomeric secreted MULT1, NKG2D is blocked from interacting with other membrane-bound NKG2D ligands and the receptor therefore remains in large abundance. These findings overturn previous hypotheses about how secreted ligands can affect immune responses.

Science 348, 136–139 (2015)