Z Gastroenterol 2019; 57(01): e80-e81
DOI: 10.1055/s-0038-1677263
5. Viral Hepatitis, Immunology
Georg Thieme Verlag KG Stuttgart · New York

Development of liver-resident memory CD8+ T cells in acute-resolving and chronic viral infection of the liver

N Kallin
1   Institute of Molecular Immunology, Technische Universität München, Klinikum rechts der Isar, Germany
,
M Bosch
1   Institute of Molecular Immunology, Technische Universität München, Klinikum rechts der Isar, Germany
,
K Manske
1   Institute of Molecular Immunology, Technische Universität München, Klinikum rechts der Isar, Germany
,
S Donakonda
1   Institute of Molecular Immunology, Technische Universität München, Klinikum rechts der Isar, Germany
,
D Wohlleber
1   Institute of Molecular Immunology, Technische Universität München, Klinikum rechts der Isar, Germany
,
PA Knolle
1   Institute of Molecular Immunology, Technische Universität München, Klinikum rechts der Isar, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2019 (online)

 

Question:

Tissue-resident memory (TRM) CD8 T cells are a recently identified memory T cell population which – in contrast to central memory and effector memory T cells – do not recirculate, but persist in non-lymphoid tissues and provide a fast immune response in case of re-exposure to the same pathogen. Several studies have described a crucial role for virus-specific TRM cells for limiting viral infection to the local tissue sites and thereby providing protection, which was so far mainly shown for barrier tissues and secondary lymphoid organs. We investigated the formation of TRM cells in the liver, target for hepatotropic viruses like Hepatitis B Virus, and aimed for comparing TRM cell formation in acute-resolved versus chronic infection of the liver using an adenovirus-based infection model.

Methods:

Mice were infected with hepatotropic adenoviral vectors encoding for ovalbumin and the reporter gene luciferase under either the CMV- or the hepatocyte-specific TTR-promoter, which led to acute-resolving or chronic viral liver infection, respectively, as detected by bioluminescent imaging. Transfer of 100 naïve CD45.1+ Ovalbumin-specific OT-I CD8 T cells before infection simplified tracking of the immune response. OT-I T cells were characterized by flow cytometry from blood, spleen and liver at different time points post infection.

Results:

During acute-resolving viral liver infection, two virus-specific CD8 T cell populations emerged in the liver, representing CX3CR1+ effector memory (TEM) and CXCR6+CD69+ tissue-resident memory (TRM) T cells. Whereas both cell populations were equally able to secrete cytokines upon ex vivo restimulation, only CXCR6+ T cells showed high levels of Granzyme B and direct killing ability ex vivo, which represent important TRM characteristics. Furthermore, CXCR6+CD69+ T cells were found exclusively in the liver, while CX3CR1+ T cells were also detected in the spleen.

Importantly, CX3CR1+ T cells did not form during chronic viral infection of the liver, indicating that CX3CR1+ cells were critical for viral clearance. Interestingly, however, chronic infection was accompanied by the formation of a liver-restricted virus-specific T cell population, which was present in the livers up to d100 despite constant antigen expression by hepatocytes. Characterization of these cells revealed them to share a TRM phenotype, being CXCR6+ and CD69+. However, the TRM-like cells did not express Granzyme B and failed to respond to ex vivo restimulation while expressing high levels of inhibitory receptors, suggesting that they represent a functionally adapted T cell population unique to chronically infected liver tissue.

Conclusions:

By recapitulating acute-resolved and chronic viral liver infection with the described models, we were able to distinguish and to follow up different long-lived hepatic CD8 T cell populations in both settings. TEM-like cells only emerged during acute-resolving infection, indicating their importance for successful viral clearance of primary infection. Interestingly, TRM-like populations developed in both settings, although exhibiting differences with regard to their functional potential. Further analysis is focused on functionally adapted TRM cells in chronic infection and their potential as target for therapeutic vaccination.