Natural killer cells (NK cells) carry activating and inhibitory receptors on their surface

Question

A. What property of NK cells do these receptors activate or inhibit, respectively? Explain your answer.
B. How are NK cells thought to use these receptors to recognize and eliminate virus-infected cells?
C. Why are the actions of NK cells categorized as innate immunity, and what do we know of their specificity for MHC class I molecules?
D. Why do the NK cells of the recipient of an organ transplant sometimes attack the transplanted tissue?

Answer 1

A. The killing activity of the NK cell. Like cytotoxic T cells, NK cells can kill other cells by releasing molecules that induce apoptosis. When an activating receptor on an NK cell recognizes its ligand on the surface of a target cell, this tends to activate the killing function of the NK cell. But when an inhibitory receptor also recognizes its ligand on the target cell, this tends to inhibit the killing activity of the NK cell, even if activating receptors are also engaged. Whether the NK cell kills the target cell depends on the balance between the activating and inhibiting signals. The known ligands for the inhibitory receptors are MHC class I molecules, and if there are normal levels of these molecules on the target-cell surface, the cell is not killed.
B. Virus-infected cells often have lower levels of MHC class I molecules on their surface. This feature is thought to be exploited by NK cells, which are continually monitoring levels of MHC class I molecules on host cells. When an NK cell finds a cell that lacks or has decreased MHC class I on its surface, the signals from the activating receptors predominate over those from the inhibitory receptors and the target cell is killed. Some viruses encode proteins that mimic MHC class I molecules and interfere with NK-cell attack by ligation of the NK cells' inhibitory receptors.
C. The actions of NK cells are considered part of innate immunity because NK cells can, in principle, act against any virus-infected cell: their killing activity is not dependent on the recognition of viral protein epitopes. In addition, NK cells are already present and ready to act immediately after they encounter an infected cell. Although there are large numbers of different inhibitory and activating receptors in the NK-cell repertoire, none of these receptors is encoded by a rearranging gene, and in most cases the receptors specifically recognize HLA allotypes and are relatively insensitive to the peptides bound.
D. Individual inhibitory NK-cell receptors are specific for particular allotypes of a given MHC class I molecule. The NK-cell repertoire of a person seems to be tailored to their own MHC tissue type, so that all NK cells in that person will carry at least one inhibitory receptor recognizing one of the person's own HLA class I molecules. This ensures that NK cells do not attack the healthy tissues of their own body. However, because MHC class I molecules are highly polymorphic, one person may have HLA class I allotypes that are not recognized by all the NK cells from another individual. If a tissue transplant is not matched exactly for HLA class I, therefore, some of the recipient's NK cells may not recognize the HLA class I molecules on the transplanted tissue and will attack it.