Development of liver-resident CD8 T cells during persistent viral liver infection results in functional adaptation

Question:

Tissue-resident CD8 memory T cells (T_RM) are described to populate parenchymal organs and to be essential for an effective immune response against pathogen re-challenge. However, the role of T_RM cells in viral infections of the liver, like chronic Hepatitis B Virus (HBV) infection, is largely unknown. We aimed at monitoring and characterizing the formation of liver-resident T cell populations upon acute-resolving or chronic viral infection of the liver for OVA-based infection models as well as chronic Adeno-HBV infection in mice.

Methods:

C57BL/6 mice were infected with liver-targeting adenoviral vectors encoding the model antigen ovalbumine under the CMV-, or the hepatocyte-restricted TTR-promoter to achieve acute-resolving or chronic viral infection, respectively. At different time points, virus-specific T cells from spleen and liver were analysed with respect to phenotypic and functional parameters. Similarly, mice were infected with a chronic dose of Adeno-HBV after having received naïve HBVcore-antigen-specific CD8 T cells and analysed accordingly.

Results:

Upon resolved infection, remaining virus-specific CD8 T cells in the liver subdivided into a CX₃CR1⁺ effector-memory and a CXCR6⁺ CD69⁺ liver-resident memory population that could be clearly distinguished by phenotypic and functional analysis. In contrast, during chronic liver infection, virus-specific T cells were expanded and maintained exclusively in the liver. These cells exhibited a CXCR6⁺ CD69⁺ T_RM-like phenotype along with a functional adaptation characterized by low Granzyme B levels, inability to secrete cytokines and high expression of inhibitory receptors. Similar results were obtained for persistent Adeno-HBV infection where we confirmed the establishment of a virus-specific CD8 T cell population in the liver that shares T_RM-characteristics, but exhibits functional impairment.

Conclusion:

Our results suggest that the development of CXCR6₊ liver-resident T cells occurs not only in the course of resolving, but also during chronic viral infection of the liver. In a chronic setting, however, CXCR6⁺ cells do not represent a functional T_RM population, but exhibit attenuated effector functions that presumably reflect adaptation to the persistent viral infection. On-going work is dedicated to define the mechanisms of T_RM development during chronic infection and to find ways for reverting T cell attenuation through adequate stimulation.