HCV immunology–Death and the maiden T cell

Abstract

Cellular immune responses play an important role in the control of hepatitis C virus (HCV), although in the majority of cases they ultimately fail. We examine the mechanisms by which virus-specific T cells may interact with a cell that is infected with HCV and how this interaction may explain the success and failure of the immune response. As an infected cell presenting foreign antigen, the hepatocyte will interact with a large number of lymphocytes, both by direct cell to cell contact and by indirect means through the secretion of cytokines and chemokines. These interactions may lead on the one hand to the death of infected hepatocytes or suppression of viral replication and on the other hand to the death of T lymphocytes or down regulation of their function. We suggest that activation of lymphocytes in lymphoid organs leads to generation of effector T cells (positive loop), while at the same time presentation of antigen in the liver either on hepatocytes or other specialised antigen presenting cells depresses these responses (negative loop). This model helps to explain both the specific phenotype and low frequencies of HCV specific CTL in chronic infection, through early elimination of cells before expansion and maturation can occur. The outcome of HCV infection is likely to result from the early balance between these two simultaneous loops.

Ultra‐sensitive class I tetramer analysis reveals previously undetectable populations of antiviral CD8+ T cells

“…The responses are clearly not deleted or "exhausted", but are detectable and appear to retain characteristics of "early" or immature forms. This is consistent with the idea that responses persist in vivo, but that more mature cells are recruited to the liver, where they die [18]. Alternatively, these very weak and immature ("stunted") responses may also potentially result from dysfunction of antigen-presenting cells that are unable to prime or to sustain the expansion of HCVspecific CTL, through lack of T cell help or through T cell regulation.…”

The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity

“…These findings also hold implications for the pathogenesis of other forms of immune-mediated liver injury. In particular, we (16) and others (43) have previously suggested that initial CD8 + T cell interactions within the liver might contribute to the immunopathogenesis of chronic hepatitis C viral infection. The current work indicates that primary activation of high-avidity cells within the liver may lead to impaired CTL function and reduced half-life, especially during early infection, when this is likely the predominant site of antigen presentation; cells more effectively activated in the LNs, possibly later in infection, may thus be of lower avidity, capable of inducing hepatitis but incapable of mediating viral clearance.…”

T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells

“…Intrahepatic T lymphocyte activation during early hepatitis C infection could contribute to the impaired immune response observed in chronic hepattis C virus. 9,38 Using the Met-K b and Alb-K b models, we have demonstrated that T lymphocyte activation in the liver is an inefficient process, leading to diminished cytotoxic activity and reduced cell survival, 8 a type of response consistent with immune tolerance. Based on these results, we propose that TEHLI play a critical role in mediating activation of naïve T lymphocytes by hepatocytes and in the development of tolerance.…”