A new self: MHC-class-I-independent Natural-killer-cell self-tolerance

Natural killer (NK) cell cytotoxicity is regulated by inhibitory receptors that bind self-MHC class I molecules. The absence of MHC class I expression causes lysis of cells, as described by the 'missing-self' hypothesis.Some aspects of NK-cell biology cannot be explained by the regulation of self-tolerance through MHC class I molecules alone, implying the existence of non-MHC-binding inhibitory receptors.2B4 is a prototypical MHC-independent inhibitory receptor. It inhibits NK-cell responses to CD48-expressing cells in mice, as well as in the absence of SAP (signalling lymphocytic activation molecule (SLAM)-associated protein) in humans. This inhibition protects against NK-cell autoreactivity.Carcinoembryonic-antigen-related cell-adhesion molecule 1 (CEACAM1) ensures NK-cell tolerance in MHC-class-I-deficient humans.Several other NK-cell inhibitory receptors recognize diverse ligands that are markers of 'self'. These receptors include some NK-cell receptor protein 1 (NKR-P1)-family members, sialic-acid-binding immunoglobulin-like lectins (SIGLECs) and glycoprotein 49 B1 (gp49B1).Non-MHC-binding inhibitory receptors regulate NK-cell responses in disease states, including infection, cancer and autoimmunity. These receptors might provide new targets for improving NK-cell responses, possibly leading to better treatments for such diseases.