Innate-like Cytotoxic Function of Bystander-Activated CD8+ T Cells Is Associated with Liver Injury in Acute Hepatitis A

Abstract

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.

No IL-18BP? Avoid HAV

“…IL-18 levels were high in the liver sections of fulminant viral hepatitis cases, with expression observed in both macrophages and hepatocytes. This result is consistent with the elevated levels of IL-18 observed in patients with acute hepatitis and HAV infection (Kim et al, 2018). Finally, the authors performed a series of in vitro studies showing that in the absence of IL-18BP, excessive NK activation by IL-18 results in the killing of human hepatocyte cells.…”

Comparison of the Clinical Features of Hepatitis A in People Living with HIV between Pandemics in 1999–2000 and 2017–2018 in the Metropolitan Area of Japan

“…We recently found that the CD4 CD8 ratio and peak ALT level were positively correlated in PLWH with acute hepatitis C (15), suggesting that a higher immune activity might lead to a more severe hepatocellular damage. The immune response to hepatitis A might also be similar since previous studies have indicated that, both, CD4 and CD8 cells were mainly associated with hepatocellular damage (16,17). At this point, it would be interesting to examine whether the disappearance of HAV will be more rapid in PLWH with high CD4 CD8 ratios than in those with low CD4 CD8 ratios; we are currently investigating this possibility.…”

DOCK2 sets the threshold for entry into the virtual memory CD8+T cell compartment by negatively regulating tonic TCR triggering

“…CD8.4 mice, expressing CD8 fused to a CD4-derived intracellular domain, exhibit higher levels of CD8-Lck coupling and have an expanded CD8 + virtual memory compartment, suggesting that the intrinsic sensitivity of the TCR signaling machinery can regulate the size of the CD8 + virtual memory compartment (Drobek et al, 2018). Virtual memory cells also provide antigenindependent innate-like bystander protection in the context of intracellular infection (White et al, 2016), and contribute to protective immunity in mice (Berg et al, 2003;Chu et al, 2013) and humans (Kim et al, 2017).…”