TP05: Reconstitution of potent antiviral CD8 T cell immunity to achieve elimination of infected hepatocytes during persistent HBV infection

We identified a liver tissue-rheostat as a regulator of HBV-specific CD8 T cell immunity and discovered auto-aggressive CD8 T cells as a cause of immune-mediated tissue pathology. The project now aims to target and overcome the regulatory control function of the liver tissue-rheostat acting on HBV-specific T cells, enabling immune-mediated control of chronic HBV infection in hepatocytes and enhancing the efficacy of therapeutic vaccination. We will elucidate the role of auto-aggressive T cells for the elimination of virus-infected hepatocytes and their cooperation with virus-specific CD8 effector T cells. Together, these results will provide knowledge on how to overcome regulatory cues in the liver

Prof. Dr. Percy A. Knolle

Dudek M, Pfister D, Donakonda S, Filpe P, Garcia-Caceres C, Gruber T, Seifert G, Kabat AM, Malm JP, Reider S, Effenberger M, Roth S, Billeter AT, Muller-Stich B, Pearce EJ, Koch-Nolte F, Kaser R, Tilg H, Thimme R, Bottler T, Tacke F, Dufour JF, Haller D, Murray PJ, Heeren R, Zehn D, Bottcher JP, Heikenwalder M, Knolle PA. (2021) Auto-aggressive CXCR6(+) CD8 T cells cause liver immune pathology in NASH. Nature. 592: 444-449. doi.org:10.1038/s41586-021-03233-8.

Pfister D, Nunez NG, Pinyol R, Govaere O, Bitzer M, Ruiz de Galarreta M, Lujambio A, Dufour JF, Marron TU, Kaseb A, Kudo M, Huang YH, Djouder N, Wolter K, Zender L, Marche PN, Decaens T, Pinato DJ, Rad R, Mertens JC, Weber A, Unger K, Meissner F, Roth S, Jilkova ZM, Claassen M, Anstee QM, Amit I, Knolle PA, Becher B, Llovet JM, Heikenwalder M. (2021) NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 592: 450-456. doi.org:10.1038/s41586-021-03362-0.

Protzer U, Maini MK, Knolle PA. (2012) Living in the liver: hepatic infections. Nat Rev Immunol. 12: 201-213. doi.org:10.1038/nri3169.

Brugger M, Laschinger M, Lampl S, Schneider A, Manske K, Esfandyari D, Hüser N, Hartmann D, Steiger K, Engelhardt S, Wohlleber D, Knolle PA. (2022) High precision-cut liver slice model to study cell-autonomous antiviral defense of hepatocytes within their microenvironment. JHEP Rep. 4: 100465. doi.org:10.1016/j.jhepr.2022.100465.

Dudek M, Lohr K, Donakonda S, Baumann T, Lüdemann M, Hegenbarth S, Dübbel L, Eberhagen C, Michailidou S, Yassin A, Prinz M, Popper B, Rose-John S, Zischka H, Knolle PA. (2022) IL-6-induced FOXO1 activity determines the dynamics of metabolism in CD8 T cells cross-primed by liver sinusoidal endothelial cells. Cell Rep. 38: 110389. doi.org:10.1016/j.celrep.2022.110389.

Hackstein CP, Spitzer J, Symeonidis K, Horvatic H, Bedke T, Steglich B, Klein S, Assmus LM, Odainic A, Szlapa J, Kessler N, Beyer M, Schmithausen R, Latz E, Flavell RA, Garbi N, Kurts C, Kümmerer BM, Trebicka J, Roers A, Huber S, Schmidt SV, Knolle PA, Abdullah Z. (2023) Interferon-induced IL-10 drives systemic T-cell dysfunction during chronic liver injury. J Hepatol. 79: 150-166. doi.org:10.1016/j.jhep.2023.02.026.

Koerber N, Priller A, Yazici S, Bauer T, Cheng CC, Mijočević H, Wintersteller H, Jeske S, Vogel E, Feuerherd M, Tinnefeld K, Winter C, Ruland J, Gerhard M, Haller B, Christa C, Zelger O, Roggendorf H, Halle M, Erber J, Lingor P, Keppler O, Zehn D, Protzer U, Knolle PA. (2022) Dynamics of spike-and nucleocapsid specific immunity during long-term follow-up and vaccination of SARS-CoV-2 convalescents. Nat Commun. 13: 153. doi.org:10.1038/s41467-021-27649-y.

Wratil PR, Stern M, Priller A, Willmann A, Daechert C, Mairhofer H, Krebs S, Fingerle V, Graf A, Steininger P, Blum H, Hornung V, Liebl B, Überla K, Prelog M, Knolle PA*, Keppler OT*, Protzer U*. (2022) Three exposures to the spike protein of SARS-CoV-2 by either infection or vaccination elicit superior neutralizing immunity to all variants of concern. Nat Med. 28: 496-503. doi.org:10.1038/s41591-022-01715-4.

Project in detail +

Overcoming the loss of virus-specific CD8 T cells during chronic hepatitis B virus (HBV) infection is im-portant to gain immune control. During the last funding period we discovered together with the groups of Heikenwälder, Thimme and Böttler a so far unknown effector function of T cells in the context of sterile liver inflammation that we termed auto-aggression because T cells did not require cognate MHC-restricted interaction and T cell receptor signalling. Instead, T cells were activated through purinergic receptors responding to danger signals such as extracellular ATP released from stressed cells. These auto-aggressive T cells were responsible for driving immunopathology in the liver. Furthermore, we identified together with the groups of Thimme, Protzer, Hofmann, Z02 and Z03 a dynamic regulation of effector CD8 T cell function in the liver through non-immune cells, i.e. liver sinusoidal endothelial cells (LSECs), which we termed a “Liver Tissue-Rheostat”, because it acted in a time dynamic fashion and relied on close interaction between LSECs and virus-specific CD8 T cells recognizing their antigen on infected hepato-cytes while extending cytosolic extensions through endothelial fenestrae. This liver tissue rheostat operat-ed through induction of PKA signalling activity in T cells that prevented signalling downstream of the T cell receptor through inhibition of src kinase phosphorylation. Failure to signal through the T cell receptor caused a complete loss of function in virus-specific CD8 T cells that were in close contact with the liver tissue rheostat during persistent infection. For these discoveries, the central projects (Z02 and Z03) were essential. During the next funding period we will build on these key findings and pursue three aims with the ultimate goal to enhance CD8 T cell-mediated control of HBV infection together with our collaborators in TRR179 Thimme, Hofmann, Böttler, Bengsch, Protzer/Wettengel, Wohlleber, Protzer/Kosinska, Bartenschlager and the Z02 and Z03 projects. The first aim is to target and overcome the regulatory control function of our recently identified "Liver Tissue-Rheostat" acting on HBV-specific T cells, thereby enabling immune-mediated control of chronic HBV infection in hepatocytes. This will be particularly relevant to enhance the efficacy of therapeutic vaccination, which will be performed together with Protzer/Kosinska, Hofmann and Thimme. The second aim is to elucidate the role of auto-aggressive T cells, which we first described in sterile inflammation, during immune-mediated elimination of virus-infected hepatocytes and their cooperation with virus-specific CD8 effector T cells. In the third aim, we will unravel how low effector function in conventional T cells can be overcome by employing T cell auto-aggression targeting infected hepatocytes.
Together, the results from this project will provide key knowledge on how to overcome regulatory cues in the liver and strengthen the effector function of HBV-specific CD8 T cells to eliminate HBV-infected hepatocytes