How do natural killer cells identify their target cells?

Natural killer (NK) cells primarily identify their target cells through the lack of MHC I molecules on the surface of potential target cells. MHC I molecules are present on most healthy nucleated cells and serve as a "self" identifier that helps the immune system recognize which cells belong to the body. When cells become infected by viruses or transformed due to cancer, they often downregulate or lose MHC I expression, making them less visible to cytotoxic T cells, which rely on MHC I to recognize and eliminate these abnormal cells. However, NK cells are uniquely equipped to recognize and attack cells that do not display MHC I, allowing them to eliminate infected or malignantly transformed cells that might evade other immune responses.

While stress markers can also contribute to activating NK cells, it is the absence of MHC I that serves as the primary signal they use to distinguish healthy cells from those that pose a threat. High levels of cytokines can indicate an immune response but are not the primary means by which NK cells identify their targets. MHC II molecules, on the other hand, are not directly involved in NK cell recognition as they are typically involved with helper T cell responses.