Virus-specific CD8+ T cells are important effector cells that determine the outcome and pathogenesis of viral hepatitis either leading to an acute resolving or a chronic infection with life-threatening immune-mediated consequences like liver cirrhosis, end-stage liver disease or liver cancer. In chronic viral hepatitis virus-specific CD8+ T cells are negatively regulated, commonly referred to as “exhausted”, and there-fore fail to clear the virus. In the first funding period we, together with Hofmann, demonstrated that exhausted virus-specific CD8+ T cells obtained from patients with chronic hepatitis B virus (HBV) or chronic hepatitis C virus (HCV) infection are not homogeneous but rather consist of more severe-ly/terminally exhausted and memory-like subsets. Furthermore, in the second funding period we found that long-living memory-like subsets retain a molecular signature of T cell exhaustion like a chronic scar after treatment-mediated cure of viral hepatitis, in particular after DAA-mediated elimination of chronic HCV infection (in collaboration with Hofmann, Bartenschlager and Z03). Additionally, together with Bengsch and Hofmann, we showed that the thymocyte selection-associated high mobility group box protein TOX is an important regulator of this chronic scar also beyond chronic HCV infection linking persistent antigen recognition to the exhausted phenotype, epigenetic imprinting and T cell longevity. Moreover, we have learnt that TOX does not act in an isolated manner, but is rather involved in a rewired network of transcriptional and epigenetic regulators, since it can also be associated with an effector in-stead of an exhausted T cell response (in collaboration with Hofmann, Neumann-Haefelin).
Based on these observations, we hypothesize that identifying the infection-specific and overarching regulatory feedback loops and determinants of T cell scarring in chronic viral hepatitis will provide us with a toolbox to re-direct exhausted T cell responses e.g., in the context of chronic HBV or HBV/HDV infection for which curative treatment options are missing. Hence, in the next funding period our overall aim is to define T cell intrinsic and extrinsic regulators of HCV-specific CD8+ T cell scarring. Together with Knolle and Bengsch, we will study metabolic factors, states and regulators that affect T cell scarring e.g., intrinsi-cally expressed glycolytic enzymes such as enolase or extrinsic acetate and lactate (metabolic T cell scarring). We also investigate transcriptional-epigenetic feedback loops regulating maintenance vs. functional adaptation of T cell scarring, together with Z03, Wohlleber and Hofmann. Candidate rheostats of T cell scarring, besides TOX, are HIF1a, NFATc1, EOMES, BATF and BACH2. Furthermore, we address the question whether scarring is also present and relevant in CD8+ T cells beyond chronic HCV infection (in collaboration with Neumann-Haefelin/Luxenburger and Protzer/Kosinska) and for CD4+ T cells (in collaboration with Böttler and Z03). For this, we make use of our access to a comprehensive collection of clinical samples from multiple viral hepatitis cohorts, facilitated by our large biobank (FREEZE-HBUF), and apply ex vivo cutting-edge multi-omic approaches (including single-cell RNA and ATAC sequencing as well as CyTOF, together with Z03 and Bengsch) and in vitro cell culture models (together with Bartenschlager, Lohmann, Hofmann). Overall, we gain further insights into general mechanisms of T cell scarring with implications for therapeutic and preventive strategies in viral hepatitis.