Vα14iNKT cell deficiency prevents acetaminophen-induced acute liver failure by enhancing hepatic glutathione and altering APAP metabolism.

Acetaminophen (APAP) overdose is widely regarded as a major cause of acute liver failure in the United States. Intentional or accidental overdose of APAP in man or rodent elicits direct hepatocellular injury that is accompanied by hepatic depletion of the antioxidant, glutathione (GSH). In recent years, the innate immune response has also been shown to promote the development of APAP hepatotoxicity via indirect liver damage.

The ROS scavenger, NAC, regulates hepatic Vα14iNKT cells signaling during Fas mAb-dependent fulminant liver failure.

Uncontrolled systemic activation of the immune system is an early initiating event that leads to development of acute fulminant liver failure (FLF) in mice after treatment with agonistic Fas mAb. In this study, we demonstrate that treatment of mice with N-acetylcysteine (NAC), an ROS scavenger and glutathione (GSH) precursor, almost completely abolished Fas mAb-induced FLF through suppression of Vα14iNKT cell activation, IFN-γ signaling, apoptosis and nitrotyrosine formation in liver. In addition, enrichment of the liver with GSH due to Vα14iNKT cells deficiency, induced an anti-inflammatory response in the liver of Jα18(-/-) mice that inhibited apoptosis, nitrotyrosine formation, IFN-γ signaling and effector functions.

V(alpha)14iNKT cells promote liver pathology during adenovirus infection by inducing CCL5 production: implications for gene therapy.

Replication-defective recombinant adenoviruses are the most widely studied replication-defective vectors for the potential treatment of inherited human diseases. However, broad clinical application of replication-defective adenoviruses in gene therapy is being hindered by the induction of vigorous innate and adaptive immune responses against the vector that cause deleterious effects in the liver. V(alpha)14 invariant natural killer T cells (V(alpha)14iNKT cells) are thymus-derived innate T cells at the interface between the two arms of the immune response and provide full engagement of host defense.

Toll-like receptor 3 ligand dampens liver inflammation by stimulating Valpha 14 invariant natural killer T cells to negatively regulate gammadeltaT cells.

Valpha14 invariant natural killer T (Valpha14iNKT) cells are at the interface between the innate and adaptive immune responses and are thus critical for providing full engagement of host defense. We investigated the role of polyriboinosinic:polycytidylic acid (poly I:C), a replication-competent viral double-stranded RNA mimic and a specific agonist that recognizes the cellular sensor Toll-like receptor 3 (TLR3), in regulating Valpha14iNKT cell activation. We established for the first time that hepatic Valpha14iNKT cells up-regulate TLR3 extracellularly after poly I:C treatment.

Characterization of the role of TCR gammadelta in NK cell accumulation during viral liver inflammation.

Polyinosinic-polyctidylic acid (Poly I:C) is a viral RNA mimic that can induce immune responses similar to that seen during viral infection. Although poly I:C administration into mice is associated increased NK cell infiltrates in the liver, the mechanisms underlying increased hepatic NK cell accumulation in response to poly I:C administration are incompletely defined. In the current study, we have identified a novel and important role for gammadelta T cells in driving the accumulation and activation of NK cells in the liver during poly I:C-mediated viral liver infection.