Endothelial cells express NKG2D ligands and desensitize antitumor NK responses

White blood cells called “natural killer cells” are part of the first line of immune defense. Often called NK cells for short, one job of these cells is to help prevent cancer by killing tumor cells. If an NK cell spots a tumor cell, it must become energized so that it can deliver the killing blow, which comes in the form of a packet of cell-killing “cytotoxic” granules. Yet tumor cells look very similar to healthy cells, and NK cells must be able to tell the difference to be effective. Molecules on the outer surface of the NK cell control how the cell recognizes tumors, and deliver the signals the cell needs to become energized. One of these surface molecules is called NKG2D. It interacts with “partner” molecules found on the surface of cancer cells and tells the NK cell to attack. These partner molecules are not usually found on healthy cells, helping the immune system to tell the difference. After NKG2D interacts with its partner molecules, it moves inside the NK cell. This makes the cell less able to become energized. If the NK cells do not encounter any partner molecules in healthy mice, blocking the interactions should have no effect on NKG2D levels. But now, Thompson et al. find that blocking one of these interactions increased the levels of NKG2D on the surface of NK cells in healthy mice. Further experiments revealed that NK cells in mice constantly encounter an NKG2D partner molecule called RAE-1e. A search for the source of RAE-1e in healthy mice pointed to blood vessels inside the lymph nodes. NK cells pass through theses organs as part of their normal path around the body. Thompson et al. also saw that NK cells from healthy mice were less responsive than NK cells from mutant mice that lacked RAE-1e. As a result of their encounters with RAE-1e in healthy mice, the NK cells were less able to kill tumor cells. Blocking the interaction between NKG2D and RAE-1e in mice re-energized their NK cells. More cells were able to enter tumors in these mice and the cells became better at killing tumors. Together these findings increase the current understanding of the biological processes that control NK cells. Further research may lead to new treatments for diseases like cancer. But first, scientists need to find out whether NK cells behave in the same way in humans as they do in mice. If so, developing ways to block the interaction could re-energize human NK cells to better kill cancer cells.