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.

Abstract-The pathogenic role of T cells in hypertension has been documented well in recent animal studies. However, the existence of T-cell-driven inflammation in human hypertension has not been confirmed. Therefore, we undertook immunologic characterization of T cells from patients with hypertension and measured circulating levels of C-X-C chemokine receptor type 3 chemokines, which are well-known tissue-homing chemokines for T cells. We analyzed immunologic markers on T cells from patients with hypertension by multicolor flow cytometry. We then measured circulating levels of the C-X-C chemokine receptor type 3 chemokines, monokine induced by γ interferon (IFN), IFN γ-induced protein 10, and IFN-inducible T-cell α chemoattractant, in patients with hypertension and in age-and sex-matched control subjects by the cytometric bead array method. In addition, we examined histological features of IFN-inducible T-cell α chemoattractant expression from renal biopsy specimens of patients with hypertensive nephrosclerosis and control subjects. The total T-cell population from patients with hypertension showed an increased fraction of immunosenescent, proinflammatory, cytotoxic CD8 + T cells. Circulating levels of C-X-C chemokine receptor type 3 chemokines were significantly higher in patients with hypertension than in control subjects. Furthermore, immunohistochemical staining revealed increased expression of the T-cell chemokine, IFN-inducible T-cell α chemoattractant, in the proximal and distal tubules of patients with hypertensive nephrosclerosis. Immunosenescent CD8 + T cells and C-X-C chemokine receptor type 3 chemokines are increased in human hypertension, suggesting a role for T-cell-driven inflammation in hypertension. A more detailed characterization of CD8 + T cells may offer new opportunities for the prevention and treatment of human hypertension. (Hypertension. 2013;62:126-133.)

Hepatitis C virus (HCV) infection results in liver injury and long‐term complications, such as liver cirrhosis and hepatocellular carcinoma. Liver injury in HCV infection is believed to be caused by host immune responses, not by viral cytopathic effects. Tumor necrosis factor‐alpha (TNF‐α) plays a pivotal role in the inflammatory processes of hepatitis C. TNF‐α induces cell death that can be ameliorated by nuclear factor kappaB (NF‐κB) activation. We investigated the regulation of TNF‐α signal transduction in HCV‐infected cells and identified HCV proteins responsible for sensitization to TNF‐α‐induced cell death. We studied the effect of HCV infection on TNF‐α signal transduction using an in vitro HCV infection model (JFH‐1, genotype 2a) with Huh‐7 and Huh‐7.5 cells. We found that TNF‐α‐induced cell death significantly increased in HCV‐infected cells. HCV infection diminished TNF‐α‐induced phosphorylation of IκB kinase (IKK) and inhibitor of NF‐κB (IκB), which are upstream regulators of NF‐κB activation. HCV infection also inhibited nuclear translocation of NF‐κB and expression of NF‐κB‐dependent anti‐apoptotic proteins, such as B‐cell lymphoma—extra large (Bcl‐xL), X‐linked inhibitor of apoptosis protein (XIAP), and the long form of cellular‐FLICE inhibitory protein (c‐FLIP). Decreased levels of Bcl‐xL, XIAP, and c‐FLIP messenger RNA and protein were also observed in livers with chronic hepatitis C. Transfection with plasmids encoding each HCV protein revealed that core, nonstructural protein (NS)4B, and NS5B attenuated TNF‐α‐induced NF‐κB activation and enhanced TNF‐α‐induced cell death. Conclusion: HCV infection enhances TNF‐α‐induced cell death by suppressing NF‐κB activation through the action of core, NS4B, and NS5B. This mechanism may contribute to immune‐mediated liver injury in HCV infection. (HEPATOLOGY 2012;56:831–840)

The size of the Treg pool was contracted during AHA, resulting from apoptosis of Tregs induced by a Fas-mediated mechanism. Decrease in Treg numbers led to reduced suppressive activity of the Treg pool and consequently resulted in severe liver injury during AHA.

BackgroundAsthmatic nasal polyps primarily exhibit eosinophilic infiltration. However, the identities of the immune cells that infiltrate non-asthmatic nasal polyps remain unclear. Thus, we thought to investigate the distribution of innate immune cells and its clinical relevance in non-asthmatic chronic rhinosinusitis (CRS) in Korea.MethodsTissues from uncinate process (UP) were obtained from controls (n = 18) and CRS without nasal polyps (CRSsNP, n = 45). Nasal polyps (NP) and UP were obtained from CRS with nasal polyps (CRSwNP, n = 56). The innate immune cells was evaluated by immunohistochemistry such as, eosinophil major basic protein (MBP), tryptase, CD68, CD163, CD11c, 2D7, human neutrophil elastase (HNE) and its distribution was analyzed according to clinical parameters.ResultsIn comparisons between UP from each group, CRSwNP had a higher number of MPB+, CD68+, and CD11c+ cells relative to CRSsNP. Comparisons between UP and NP from CRSwNP indicated that NP have a higher infiltrate of MBP+, CD163+, CD11c+, 2D7+ and HNE+ cells, whereas fewer CD68+ cells were found in NP. In addition, MBP+ and CD11c+ cells were increased from UP of CRSsNP, to UP of CRSwNP, and to NP of CRSwNP. Moreover, in UP from CRSwNP, the number of MBP+ and CD11c+ cells positively correlated with CT scores. In the analysis of CRSwNP phenotype, allergic eosinophilic polyps had a higher number of MBP+, tryptase+, CD11c+, 2D7+ cells than others, whereas allergic non-eosinophilic polyps showed mainly infiltration of HNE+ and 2D7+ cells.ConclusionsThe infiltration of MBP+ and CD11c+ innate immune cells show a significant association with phenotype and disease extent of CRS and allergic status also may influences cellular phenotype in non-asthmatic CRSwNP in Korea.