6 However, the mechanism by which NK cells are activated and contribute to the pathogenesis of autoimmune liver disease was largely unknown until Shimoda et al.7 published their recent data in this issue of HEPATOLOGY. NK cells represent a small percentage of blood lymphocytes that have the ability to kill cancer cells and virus-infected

cells through release of small cytoplasmic granules of perforin, granzymes, Fas ligand, or TRAIL (tumor necrosis factor–related apoptosis-inducing ligand). In contrast to the low percentage of NK cells in peripheral blood, liver lymphocytes are enriched in NK cells, accounting for 15%-30% of all liver lymphocytes that play an important role in immunosurveillance against tumor transformation and viral LY2835219 clinical trial infection in the liver.8 It was originally thought that without requirement of activation, NK cells can kill target cells that Rapamycin molecular weight are

missing “self” markers of the major histocompatibility complex class I. It is now known that NK cells do require activation before killing target cells. Activation of NK cells is determined when there is an imbalance of signals from stimulatory and inhibitory receptors on the NK cells that interact with corresponding stimulatory and inhibitory ligands from target cells, respectively.9 If the stimulatory signal dominates over the inhibitory signal, NK cells become activated and Glutathione peroxidase kill target cells. NK cell stimulatory receptors include NKG2D, NKp46, NKp30, NKp44, and DNAC accessory molecule-1 (CD226). Among them, the NKG2D is the best characterized and is known to be activated by stimulatory ligands including

RAE-1 (retinoic acid early inducible gene 1), histocompatibility 60, UL-16 binding protein-like transcript 1 expressed on mouse target cells, and MICA/B (major histocompatibility complex class I–related molecule A/B) and UL-16 binding proteins expressed on human target cells.9, 10 In addition, NK cells are also activated by a variety of cytokines including interferons (IFNs), interleukin-2 (IL-2), IL-18, IL-12, and IL-15. Evidence has shown that type I IFNs play a key role in inducing NK cell activation, which in turn mediates death to virus-infected hepatocytes and inhibits hepatitis virus replication.11, 12 Additionally, several Toll-like receptor (TLR) ligands can directly activate NK cells13 or stimulate surrounding antigen-presenting cells to produce cytokines that subsequently induce NK cell activation indirectly.14, 15 TLRs are a group of proteins that recognize well-conserved microbial structures known as pathogen-associated molecular patterns. The TLR1, TLR2, TLR4, TLR5, TLR6, TLR10, and TLR11 proteins (TLR11 is present in mice, but not humans) are associated with plasma membranes and recognize bacterial cell wall components such as bacterial flagellin and viral particles.