Innocent spectators, helping hands or a fifth column? Acute hepatitis A infection reveals important insights into bystander T cells.

Kim and colleagues studied a large cohort of adults with acute symptomatic HAV infection. They found pervasive and profound CD8 T cell activation in the blood of these patients, together with increased T cell proliferation and expression of cytotoxic molecules in a substantial proportion and often the majority of circulating CD8 T cells. The degree of overall activation, proliferation and cytotoxic capacity was tightly correlated with liver damage, as measured by ALT serum levels. Critically, they showed that this activated CD8 T cell phenotype was not limited to HAV-specific T cells but was found on multiple HAV-unrelated specificities they tested, i.e. CD8 T cells targeting influenza A virus (IAV), cytomegalovirus (CMV) and Epstein-Barr Virus (EBV). They then demonstrated that serum levels of IL-15 were elevated in acute HAV-infected patients and that IL-15 is produced by HAV-infected cells in the liver and in in vitro cell culture. Together with the observation that IL-15 had the greatest potency to induce the same phenotypic and functional profiles of CD8 T cells in vitro this suggests a key role for this cytokine in the induction of this general CD8 T cell activation. The effect of IL-15 was shown to be independent of TCR stimulation, but rather mediated through the upregulation of NKG2D and NKp30 on HAV-unrelated virus-specific T cell populations, thus suggesting an innate-like rather than an antigen-specific cytotoxic T cell phenotype. The potential for these non-HAV-specific CD8 T cells to inflict liver damage via an NKG2D based innate-like mechanism was further supported by the expression of the corresponding NKG2D receptors MIC-A and B on hepatocytes from HAV-infected livers. Indeed, the number of activated non-specific bystander CD8 T cells corresponded with the degree of liver damage, whereas the frequency of HAV-specific T cells seemed more correlated with viral control than with pathology. Overall, this study strongly supports a role for bystander CD8 T cell activity in acute HAV infection disease pathogenesis and identifies secretion of IL-15 by HAV-infected hepatocytes as the origin of an innate-like CD8 bystander response. This article is protected by copyright. All rights reserved.