Virus-Specific CD8+ T Cells in the Liver: Armed and Ready to Kill

Abstract

Influenza A virus infection of C57BL/6 mice is a well-characterized model for studying CD8+ T cell-mediated immunity. Analysis of primary and secondary responses showed that the liver is highly enriched for CD8+ T cells specific for the immunodominant H2DbNP366–374 (DbNP366) epitope. Functional analysis established that these liver-derived virus-specific CD8+ T cells are fully competent cytotoxic effectors and IFN-γ secretors. In addition, flow cytometric analysis of early apoptotic cells showed that these influenza-specific CD8+ T cells from liver are as viable as those in the spleen, bronchoalveolar lavage, mediastinal lymph nodes, or lung. Moreover, cytokine profiles of the influenza-specific CD8+ T cells recovered from different sites were consistent with the bronchoalveolar lavage, rather than liver population, being the most susceptible to activation-induced cell death. Importantly, adoptively transferred influenza virus-specific CD8+ T cells from the liver survived and were readily recalled after virus challenge. Together, these results show clearly that the liver is not a “graveyard” for influenza virus-specific CD8+ T cells.

Effector Function-Deficient Memory CD8+ T Cells Clonally Expand in the Liver and Give Rise to Peripheral Memory CD8+ T Cells

“…Alternatively, the liver and the bone marrow are responsible for homeostatic expansion of nonoverlapping memory T cell subsets, or that renewed memory T cells from the liver and bone marrow may be functionally distinct. Reports contrasting the long-held view that the liver is a graveyard for activated T cells have been published (37)(38)(39). CD8 + memory T cells do more than gain entry and survive in the liver, our results show that they actually grow in the liver.…”

Early Intrahepatic Accumulation of CD8+ T Cells Provides a Source of Effectors for Nonhepatic Immune Responses

“…The present study advances these findings by showing significant influenza-specific T cell accumulation at very early phases even before the systemic response is fully established, as well as the ability of these accumulating cells to exit the liver and to generate viable memory populations. This indicates an active role for the liver in contributing to mounting immune responses, which has been suggested (15) but not demonstrated.…”

“…Keating et al (15) have concurrently found high viability among Ag-specific T cells in the liver at peak and resolution phases. Thus, mounting evidence indicates that during resolution, the liver does not merely harbor apoptosing T cells.…”

Hepatitis B virus as a gene delivery vector activating foreign antigenic T cell response that abrogates viral expression in mouse models

“…24,25 Nevertheless, an increasing number of studies have demonstrated the presence of fully functional effector T cells in the liver. 26,27 Virus-specific T cells may be retained in the liver even though the virus is not known to infect this organ, and they can cause resulting bystander hepatitis even when hepatocytes do not express the antigen recognized by the T cells. [27][28][29] This was also evidenced in our study of HBsAg transgenic mice.…”

“…26,27 Virus-specific T cells may be retained in the liver even though the virus is not known to infect this organ, and they can cause resulting bystander hepatitis even when hepatocytes do not express the antigen recognized by the T cells. [27][28][29] This was also evidenced in our study of HBsAg transgenic mice. First, the peripherally activated T cell response, which mostly comprised Flu-specific T cells but no HBsAg-specific T cells, may have partially reduced HBsAg production.…”