Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis

Abstract

CD8 T cells protect the liver against viral infection, but can also cause severe liver damage that may even lead to organ failure. Given the lack of mechanistic insights and specific treatment options in patients with acute fulminant hepatitis, we develop a mouse model reflecting a severe acute virus-induced CD8 T cell-mediated hepatitis. Here we show that antigen-specific CD8 T cells induce liver damage in a perforin-dependent manner, yet liver failure is not caused by effector responses targeting virus-infected hepatocytes alone. Additionally, CD8 T cell mediated elimination of cross-presenting liver sinusoidal endothelial cells causes endothelial damage that leads to a dramatically impaired sinusoidal perfusion and indirectly to hepatocyte death. With the identification of perforin-mediated killing as a critical pathophysiologic mechanism of liver failure and the protective function of a new class of perforin inhibitor, our study opens new potential therapeutic angles for fulminant viral hepatitis.

TIGIT limits immune pathology during viral infections

“…6D, E). An important mediator of tissue damage is perforin, which was shown to contribute to CD8 + T cell-dependent hepatitis in a model of virally induced immune pathology 41 and to CD8 + T cell-driven immunopathology in PD-L1-deficient mice upon LCMV infection 42 . Therefore, we speculated that TIGIT might be involved in regulating perforindependent tissue damage following acute virus infection.…”

Perforins Expression by Cutaneous Gamma Delta T Cells

“…Location in the cell Intracellular cytolytic granules (39) Membranes of intracellular endosomes (46,47) Function in GD T cells Lysis of transformed or infected cells (39)(40)(41) Destruction of intracellular bacteria (46,47) Stimulatory factors Surface receptors: -GD TCR 53 suffering from these illnesses. Compounds identified as Perforin inhibitors in NK and AB T cells include diarylthiophenes and benzenesulfonamide based therapeutics (83)(84)(85). In short, cutaneous GD T cells express Perforin upon activation and this activation can be achieved through a variety of mechanisms including stimulation of the TCR, ligation of costimulatory molecules, and cytokine stimulation ( Table 1).…”

“…Given the deleterious effects of Perforin expressing cells in the context of autoimmune and inflammatory disorders, blocking therapeutics targeting Perforin may benefit patients suffering from these illnesses. Compounds identified as Perforin inhibitors in NK and AB T cells include diarylthiophenes and benzenesulfonamide based therapeutics ( 83 – 85 ). In short, cutaneous GD T cells express Perforin upon activation and this activation can be achieved through a variety of mechanisms including stimulation of the TCR, ligation of costimulatory molecules, and cytokine stimulation ( Table 1 ).…”

Recent Progress in Designing Halide-Perovskite-Based System for the Photocatalytic Applications

“…More recently, numerous works using halide perovskite for photocatalysis have been reported (Chen et al, 2019 ; Liang et al, 2019 ; Huynh et al, 2020 ; Kim et al, 2020 ; Wang H. et al, 2020 ). Despite the excellent optoelectronic properties, the halide perovskite suffers some disadvantages such as the crystal structure instability (Chen et al, 2018 ), poor moisture tolerance (Smith et al, 2014 ), lack of catalytic active sites (Tang et al, 2019 ), and inefficient carrier separation for nanoscale unit (Jiang et al, 2015 ). Some of which may influence the photocatalytic process.…”