Checkpoint blockade enhances effector T cell function and has elicited long-term remission in a subset of patients with a broad spectrum of cancers. TIGIT is a checkpoint receptor thought to be involved in mediating T cell exhaustion in tumors; however, the relevance of TIGIT to the dysfunction of natural killer (NK) cells remains poorly understood. Here we found that TIGIT, but not the other checkpoint molecules CTLA-4 and PD-1, was associated with NK cell exhaustion in tumor-bearing mice and patients with colon cancer. Blockade of TIGIT prevented NK cell exhaustion and promoted NK cell-dependent tumor immunity in several tumor-bearing mouse models. Furthermore, blockade of TIGIT resulted in potent tumor-specific T cell immunity in an NK cell-dependent manner, enhanced therapy with antibody to the PD-1 ligand PD-L1 and sustained memory immunity in tumor re-challenge models. This work demonstrates that TIGIT constitutes a previously unappreciated checkpoint in NK cells and that targeting TIGIT alone or in combination with other checkpoint receptors is a promising anti-cancer therapeutic strategy.

Background: Galectin-3, a ␤-galactoside-binding protein, is expressed by many types of tumor cells. Results: Galectin-3 secreted from a tumor works as a soluble inhibitory ligand of the NK cell receptor NKp30 to inhibit NK cell immune responses against tumors. Conclusion: Galectin-3 regulates the antitumor immunity of human NK cells. Significance: This novel mechanism may provide a new therapeutic target for tumor treatment.

Hepatitis B virus (HBV) persistence is a fundamental process in chronic HBV infection and a key factor in all related liver diseases; however, the mechanisms have yet to be elucidated. We studied the role of TLR2 in HBV persistence using a well-established HBV-carrier mouse model generated by hydrodynamically injecting a phospho–adeno-associated virus/HBV1.2 plasmid into mice. We found that a genetic deficiency in TLR2 improves HBV elimination, whereas activating TLR2 led to more stable HBV persistence, suggesting that TLR2 activation is critical in HBV persistence. Furthermore, we noted that TLR2 activation could inhibit CD8+ T cell function, causing the exhaustion phenotype in HBV-carrier mice, because TLR2 deficiency might rescue CD8+ T cell function in a cellular adoptive experiment. TLR2 expression on Kupffer cells (KCs) was upregulated in HBV-carrier mice, which accounts for HBV persistence, because the difference in anti-HBV immunity between HBV-carrier wild-type and Tlr2−/− mice did not exist after KC depletion. In addition, similar to TLR2 deficiency, after KC depletion, CD8+ T cells were more efficiently activated in HBV-carrier mice, leading to rapid HBV elimination. KCs produced more IL-10 upon TLR2 activation in response to direct hepatitis B core Ag stimulation, and the elevated IL-10 inhibited CD8+ T cell function in HBV-carrier mice, because IL-10 deficiency or anti–IL-10R treatment resulted in CD8+ T cells with stronger antiviral function. In conclusion, KCs support liver tolerance by inducing anti-HBV CD8+ T cell exhaustion via IL-10 production after TLR2 activation by hepatitis B core Ag stimulation.

Lysostaphin is effective in treating experimental endophthalmitis mediated by MRSA.

No abstract

Background: B7-H6, the ligand for NKp30, is expressed on tumor cells. Results: Tumor therapeutics promote B7-H6 expression in tumor cells and enhance tumor sensitivity to NK cell cytolysis. Conclusion: Tumor therapeutics work as stress inducers to enhance tumor sensitivity to NK cell cytolysis. Significance: These results suggest that B7-H6 could be a potential target for tumor therapy in the future.

Overactivation of innate immunity, particularly natural killer (NK) cells, is harmful to liver regeneration; however, the molecular mechanisms that limit NK cell overactivation during liver regeneration are still elusive. Here we show that a coinhibitory receptor, T cell Ig and ITIM domain (TIGIT), was selectively up-regulated on NK cells, along with high expression of its ligand, poliovirus receptor (PVR/CD155), on hepatocytes during liver regeneration. The absence of TIGIT impaired liver regeneration in vivo, along with overactivation of NK cells and higher NK-derived interferon-gamma (IFN-c) production. We also show that both depletion of NK cells and deficiency of IFN-c, but not deficiency of RAG1, rescued impaired liver regeneration caused by the absence of TIGIT. Adoptive transfer of Tigit -/-NK cells into NK-deficient Nfil3 -/-mice sufficiently led to impairment of liver regeneration. On the other hand, silencing PVR in hepatocytes rescued impaired liver regeneration caused by TIGIT deficiency in vivo, while blockade of TIGIT in NK-hepatocyte coculture increased IFN-c production by NK cells in vitro. Conclusion: TIGIT is a safeguard molecule to improve liver regeneration through negatively regulating NK-hepatocyte crosstalk. This finding suggests a novel mechanism of NK cell self-tolerance towards regenerative hyperplasia of the host. (HEPATOLOGY 2014;60:1389-1398

Commensal bacteria have been proposed to play a role in liver repair after partial (67%) hepatectomy. However, the underlying immune mechanisms remain elusive. Here, we show that liver regeneration was impaired in antibiotic (Atb) water-treated mice and this impairment strongly correlated with commensal bacterial load. Among the various Atbs used in our cocktail, ampicillin-sensitive commensal bacterial was associated with normal liver regeneration. The number of CD1d-dependent natural killer T (NKT) cells in Atb-treated hepatectomized mice was markedly increased, and these NKT cells were functionally overactivated to produce higher interferon-c. Deficiency of NKT cells or antibody blockade of the CD1d-NKT interaction increased hepatocyte proliferation, which improved liver regeneration. Importantly, an increased number of Kupffer cells were observed in Atb-treated mice, and these Kupffer cells produced higher interleukin-12, which then functioned to activate hepatic NKT cells. Interleukin-12p40 deficiency or treatment with an anti-interleukin-12 antibody significantly inhibited NKT cell overactivation and recovered liver regeneration in Atb-treated mice. Conclusion: Commensal bacteria play a critical role in maintaining Kupffer cells in a tolerant state, preventing subsequent NKT cell overactivation during liver regeneration. Moreover, our data suggest that long-term Atb use, which can impair the gut microbiota, may influence liver function by retarding liver regeneration. (HEPATOLOGY 2015;62:253-264)