Acute hepatitis A (AHA) involves severe CD8+ T cell-mediated liver injury. Here we showed during AHA, CD8+ T cells specific to unrelated viruses became activated. Hepatitis A virus (HAV)-infected ...cells produced IL-15 that induced T cell receptor (TCR)-independent activation of memory CD8+ T cells. TCR-independent activation of non-HAV-specific CD8+ T cells were detected in patients, as indicated by NKG2D upregulation, a marker of TCR-independent T cell activation by IL-15. CD8+ T cells derived from AHA patients exerted innate-like cytotoxicity triggered by activating receptors NKG2D and NKp30 without TCR engagement. We demonstrated that the severity of liver injury in AHA patients correlated with the activation of HAV-unrelated virus-specific CD8+ T cells and the innate-like cytolytic activity of CD8+ T cells, but not the activation of HAV-specific T cells. Thus, host injury in AHA is associated with innate-like cytotoxicity of bystander-activated CD8+ T cells, a result with implications for acute viral diseases.
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•During acute hepatitis A (AHA), non-HAV-specific memory CD8+ T cells are activated•Non-HAV-specific CD8+ T cells are activated by IL-15 produced by HAV-infected cells•CD8+ T cells of AHA patients exert TCR-independent, innate-like cytotoxicity•Innate-like cytotoxicity of CD8+ T cells is associated with liver injury in AHA
During acute hepatitis A, hepatitis A virus (HAV)-infected cells produce IL-15 that induces TCR-independent bystander activation of non-HAV-specific memory CD8+ T cells. These CD8+ T cells exert innate-like cytotoxicity triggered by NKG2D and NKp30 without TCR engagement. The severity of liver injury is associated with activation and innate-like cytotoxicity of non-HAV-specific CD8+ T cells, but not the activation of HAV-specific T cells. Thus, IL-15-induced bystander-activated CD8+ T cells are implicated in host injury during acute viral infection.
Bleeding is largely unavoidable following syringe needle puncture of biological tissues and, while inconvenient, this typically causes little or no harm in healthy individuals. However, there are ...certain circumstances where syringe injections can have more significant side effects, such as uncontrolled bleeding in those with haemophilia, coagulopathy, or the transmission of infectious diseases through contaminated blood. Herein, we present a haemostatic hypodermic needle able to prevent bleeding following tissue puncture. The surface of the needle is coated with partially crosslinked catechol-functionalized chitosan that undergoes a solid-to-gel phase transition in situ to seal punctured tissues. Testing the capabilities of these haemostatic needles, we report complete prevention of blood loss following intravenous and intramuscular injections in animal models, and 100% survival in haemophiliac mice following syringe puncture of the jugular vein. Such self-sealing haemostatic needles and adhesive coatings may therefore help to prevent complications associated with bleeding in more clinical settings.
Acute hepatitis A caused by hepatitis A virus (HAV) infection is accompanied by severe liver injury in adult patients, and the liver injury is associated with the production of chemokines. Herein, we ...investigated the mechanism of how HAV infection induces the production of CXCR3 and CCR5 chemokines, such as CXCL10, CCL4 and CCL5. The production of CXCL10, CCL4 and CCL5 was markedly increased by HAV (HM-175/18f) infection in the culture of primary human hepatocytes and HepG2 cells. In particular, CXCL10 was produced in HAV-infected cells, not in neighboring uninfected cells. Moreover, these chemokines were significantly increased in the sera of acute hepatitis A patients. The production of IFN-λs was also robustly induced by HAV infection, and the blocking of secreted IFN-λs partially abrogated the production of CCL4 and CCL5 in HAV-infected cells. However, CXCL10 production was not decreased by the blocking of IFN-λs. Instead, CXCL10 production was reduced by silencing the expression of RIG-I-like receptor (RLR) signal molecules, such as mitochondrial antiviral signaling protein and interferon regulatory factor 3, in HAV-infected cells. In conclusion, HAV infection strongly induces the production of helper 1 T cell-associated chemokines, particularly CXCL10 via RLR signaling, even without secreted IFNs.
Genetic polymorphisms in IFNL4 have been shown to predict responses to IFN-α-based therapy in hepatitis C virus (HCV)-infected patients. The IFNL4-ΔG genotype, which encodes functional IFN-λ4 ...protein, is associated with a poor treatment response. In the present study, we investigated the induction and biological effects of IFN-λ4 in HCV-infected hepatocytes and their association with responsiveness to IFN-α. We also studied the effects of direct-acting antiviral (DAA) treatment on IFN-λ4 expression and IFN-α responsiveness. HCV infection induced IFN-λ4 expression at mRNA and protein levels in primary human hepatocytes (PHHs). In hepatoma cells, IFNL4 gene transfection or recombinant IFN-λ4 protein treatment robustly increased the protein levels of ISG15 and USP18 in an IFNLR1-dependent manner and potently blocked IFN-α signalling. The ISG15/USP18-mediated IFN-α unresponsiveness was demonstrated by transfection of siRNAs targeting ISG15 and/or USP18. This potent IFN-λ4 effect was related to prolonged ISG expression after IFNL4 gene transfection. DAA treatment of HCV-infected PHHs reduced the expression of IFN-λs, including IFN-λ4, and restored IFN-α responsiveness. These results demonstrate that virus-induced IFN-λ4 potently blocks IFN-α signalling by inducing high protein levels of ISG15 and USP18. Moreover, the data clearly demonstrate that DAA therapy restores IFN-α responsiveness in HCV-infected cells.
Up-regulation of IFN-stimulated genes (ISGs) is sustained in hepatitis C virus (HCV)-infected livers. Here, we investigated the mechanism of prolonged ISG expression and its role in IFN ...responsiveness during HCV infection in relation to unphosphorylated IFN-stimulated gene factor 3 (U-ISGF3), recently identified as a tripartite transcription factor formed by high levels of IFN response factor 9 (IRF9), STAT1, and STAT2 without tyrosine phosphorylation of the STATs. The level of U-ISGF3, but not tyrosine phosphorylated STAT1, is significantly elevated in response to IFN-λ and IFN-β during chronic HCV infection. U-ISGF3 prolongs the expression of a subset of ISGs and restricts HCV chronic replication. However, paradoxically, high levels of U-ISGF3 also confer unresponsiveness to IFN-α therapy. As a mechanism of U-ISGF3–induced resistance to IFN-α, we found that ISG15, a U-ISGF3-induced protein, sustains the abundance of ubiquitin-specific protease 18 (USP18), a negative regulator of IFN signaling. Our data demonstrate that U-ISGF3 induced by IFN-λs and -β drives prolonged expression of a set of ISGs, leading to chronic activation of innate responses and conferring a lack of response to IFN-α in HCV-infected liver.
Abstract The performance of perovskite solar cells (PSCs) is significantly governed by the interface of perovskite layer. Therefore, a great deal of attention has been paid to the interface ...engineering of perovskite layer to improve the performance of PSC. In the meantime, KCl is one of the popular molecules being utilized for the interface treatment between SnO 2 and perovskite. In this study, we investigate the effect of UV‐ozone (UVO) treatment of KCl interlayer on the photovoltaic performance. A device employing UVO‐treated KCl shows a higher power conversion efficiency mainly based on an increased open‐circuit voltage ( V OC ). Ultraviolet photoelectron spectroscopy analysis indicates that the UVO treatment induces a rearrangement of energy level at the interface, being responsible for the increase in V OC . Accordingly, an increased charge recombination resistance is evidenced by impedance spectroscopy owing to the inhibited recombination at the SnO 2 and perovskite interface by the aid of the aligned energy level.
Abstract
Background
Direct-acting antiviral (DAA) agents can successfully treat chronic hepatitis C virus (HCV) infection. However, the ex vivo HCV-specific T-cell function following viral clearance ...remains unknown.
Methods
We investigated functional alterations and phenotypic changes in ex vivo HCV-specific CD8+ T cells with a longitudinal analysis of 41 patients with chronic HCV infection who were undergoing DAA treatment.
Results
A patient subset exhibited a significantly increased T-cell response (mainly CD8+ T cells) at week 4 of treatment. However, this increased T-cell response diminished in later weeks. Relative to pretreatment levels, the ex vivo HCV-specific CD8+ T-cell frequency decreased at 12 weeks after the end of treatment, along with a decreased antigen-experienced CD8+ T-cell population. DAA treatment increased the proliferative capacity of HCV-specific CD8+ T cells, but this change was not correlated with ex vivo function. Patients experiencing viral breakthrough or relapse exhibited defective restoration of T-cell function.
Conclusion
Our present results indicated that DAA-mediated viral clearance only transiently restored ex vivo T-cell function, suggesting a need to enhance T-cell function in DAA-treated patients.
Our study explored ex vivo T-cell responses to HCV after DAA treatment and demonstrated that DAA-mediated viral clearance only transiently restored T-cell function, suggesting a need to enhance ex vivo T-cell function in DAA-treated patients.
Immune checkpoint inhibitors (ICI) are used for the treatment of various cancers, but clinical trials of anti-programmed cell death protein 1 (PD-1) with patients with recurrent glioblastoma (GBM) ...have failed to show clinical benefits. In this study, we examined the differentiation status of CD8
tumor-infiltrating lymphocytes (TIL) from patients with primary GBM and their reinvigoration by ICIs to understand the nature of T-cell exhaustion in GBM.
We isolated TILs from 98 patients with newly diagnosed GBM and examined the expression of immune checkpoint receptors and T-cell transcription factors using flow cytometry. TILs were
stimulated with anti-CD3 in the presence of anti-PD-1 and/or anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) and their proliferation assessed.
CD8
TILs had significantly increased expression of immune checkpoint receptors, including PD-1 and CTLA-4, compared with peripheral blood CD8
T cells. Among CD8
TILs, PD-1
cells exhibited more terminally differentiated phenotypes (i.e., Eomes
T-bet
) than PD-1
cells. These data were confirmed by analyzing NY-ESO-1
-specific CD8
TILs. Evaluating the proliferation of CD8
TILs after
stimulation with anti-CD3 and anti-PD-1, we found that proliferation inversely correlated with the percentage of Eomes
T-bet
cells among PD-1
CD8
TILs. When anti-CTLA-4 was used in combination with anti-PD-1, an additional increase in CD8
TIL proliferation was observed in patients with low percentages of Eomes
T-bet
CD8
TILs, who responded well to anti-PD-1 in
assays, but not in patients with high percentages of Eomes
T-bet
CD8
TILs, who did not respond to anti-PD-1.
In primary GBM, the differentiation status of CD8
TILs determines their reinvigoration ability upon ICI treatment.
Novel TiO2 nanorods (NRs) with various lengths of 70–200 nm and uniform widths of 46–48 nm are selectively synthesized by a solvothermal reaction under a basic environment. The length of TiO2 NRs is ...reproducibly tuned by varying the concentration of tetramethylammonium hydroxide (TMAH), while the NRs in the pure anatase phase are grown in the 001 direction, caused by the preferential binding affinity of TMAH to the TiO2 (101) facet. TiO2 NRs of various lengths are then applied to form the electron transporting layer (ETL) of mesoscopic perovskite solar cells (PSCs). We found that PSC devices with NRs exhibit superior photovoltaic (PV) performance to those with conventional 46 nm-sized TiO2 nanoparticles (NP46). Particularly, the PSC with TiO2 NRs of 110 nm length (NR110) exhibits the optimum PV conversion efficiency (PCE): the average PCE is 22.64% with a V OC of 1.137 V, a J SC of 24.60 mA·cm–2, and a FF of 80.96%, while the champion PCE is 23.18%. In addition, the PSC with NR110 (PSC-NR110) reveals significantly improved long-term stability in air with a relative humidity of 40–50%. In 1000 h, its PCE is reduced by only 9% whereas that of PSC with NP46 decreases by 25%. The PSC properties analyzed by impedance spectroscopy and J–V curve measurements under dark conditions and at various light intensities provide evidence that PSC-NR110 has fewer defects and shows significantly reduced charge recombination. We discuss the advantages of NR structures in preparing the ETL of PSC devices and also explain why the charge recombination is suppressed.
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