Functional Investigation Of NK Cell Inhibitory Receptor TIGIT

NK cells is a major compartment of the innate immune system, which plays an important role in both anti-tumor and anti-virus immunity. Despite its crucial function in immune surveillance, over-activity of NK cells might cause excessive tissue damage, or even fatal organ failure.Therefore, it is vital to restrain the activity of NK cells, so as to maintain self-tolerance.Compared with our knowledge on immune tolerance of T/B cells, we know little about NK cell self-tolerance, not to mention how to harness such aspect of NK cell biology, to benefit the health of human beings. To our knowledge, mechanisms underlying self-tolerance of NK cells include inhibitory receptor-mediated pathways and activation induced cellular apoptosis. Inhibitory receptors play important regulatory role in the interaction between NK cells and accessory cells. In the liver, such cellular interactions are important aspects of NK cell-mediated innate immune responses. Through studies on the role of inhibitory receptors in NK cell-mediated hepatic innate immune response and hepatic pathology, we could hopefully better understand the way NK cells maintain self-tolerance.Major results of current study were summarized as follows:1. Inhibitory receptor TIGIT negatively regulates NK cell-Kupffer cell interaction and protects mice from acute viral hepatitis.We found that challenging mice using poly I:C, a viral dsRNA analog, in combination with hepatotoxic D-galactosamine, or after adenovirus acute infection, TIGIT was selectively upregulated on NK cells. Absence of TIGIT promoted NK cell activation and aggravated liver injury, in both an NK cell-and Kupffer cell-dependent manner. Mechanistic studies showed that PVR on Kupffer cells protected mice from liver injury caused by poly I:C/D-GalN or adenovirus, in TIGIT-dependent way. Blocking TIGIT or PVR, in in vitro NK cell-Kupffer cell co-culture system, enhanced poly I:C-induced NK cell activation and IFN-y production.2. Inhibitory receptor TIGIT negatively regulates NK cell-hepatocyte interaction and protects liver regeneration.Similar with the observations in viral/virus-like hepatic injury models, we found that TIGIT was selectively upregulated on NK cells during liver regeneration. Absence of TIGIT promoted IFN-y production by NK cells and impaired hepatocyte proliferation and liver mass gain. Such effects were NK cell-dependent and T/B cell-independent. Besides, we found that PVR on hepatocytes was upregulated around the peak of hepatocyte proliferation. The protective role of TIGIT depended on such upregulation. Finally, in vitro studies using co-culture system showed that TIGIT negatively regulated NK-hepatocyte crosstalk and IFN-y production.In conclusion, inhibitory receptor TIGIT negatively regulates NK cell-Kupffer cell/hepatocyte crosstalk and subsequent over-activity and NK cell IFN-y production, by engaging its ligand, PVR, to protect mice in acute viral hepatitis or liver regeneration, suggesting the important regulatory role of TIGIT-PVR interaction in NK cell-mediated hepatic innate immune response.