EN
Project - A02:
Antigen-independent mechanisms determining tissue damage in liver auto-immunity
Project leaders:
Prof. Dr. med. Percy Knolle &
Dr. rer. nat. Michael Dudek
Summary
The liver has unique immune functions to induce immune tolerance, but can also become a target of autoimmunity that causes liver damage and substantial morbidity and mortality. We will explore whether two recently recognised immune pathways mediating tissue damage contribute to autoimmune liver disease. We will determine the contribution of autoaggressive (aa) T cells, a recently identified, functionally distinct CD8 T cell population with tissue-destructive properties, to the development of autoimmune liver disease. Second, we will characterise the relevance of a lowered threshold to the induction of apoptosis in hepatocytes with loss of mitochondrial resistance for autoimmune liver disease.
Together with our partners in the CRC, we will employ preclinical in vivo models to obtain deep mechanistic insight into how reduced mitochondrial resilience in hepatocytes and aaT cells overcome hepatic immune regulation and contribute to liver autoimmunity. Using clinical material from patients with autoimmune liver disease, i.e., liver tissue and T cells, we will translate the mechanistic knowledge obtained in preclinical models to define novel key pathways in aaT cells and hepatocytes that determine the induction of liver damage in autoimmunity. In this way, the project aims to develop novel targeted immune intervention strategies that selectively abrogate tissue-destructive autoaggression while sparing pathogen-specific immunity and immune surveillance.
Project plan
We will investigate the conceptual question of whether autoaggressive (aa) CD8 T cells and loss of mitochondrial resilience amplify T cell responses in the liver and thereby contribute to autoimmune liver disease.
WP1: To explore the role of aaT cells in autoimmune liver disease.
WP2: To characterise decreased mitochondrial resistance in autoimmune liver disease.
WP3: To define synergistic activity of aaT cells and reduced mitochondrial resilience.
Project related publications
Limmer A, Ohl J, Kurts C, Ljunggren HG, Reiss Y, Groettrup M, Momburg F, Arnold B, Knolle PA. Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance. Nat Med 2000;6:1348-54. doi: 10.1038/82161.
Böttcher JP, Schanz O, Wohlleber D, Abdullah Z, Debey-Pascher S, Staratschek-Jox A, Höchst B, Hegenbarth S, Grell J, Limmer A, Atreya I, Neurath MF, Busch DH, Schmitt E, van Endert P, Kolanus W, Kurts C, Schultze JL, Diehl L, Knolle PA. Liver-primed memory T cells generated under noninflammatory conditions provide anti-infectious immunity. Cell Rep 2013;3:779-95. doi: 10.1016/j.celrep.2013.02.008. Epub 2013 Mar 14.
Huang LR, Wohlleber D, Reisinger F, Jenne CN, Cheng RL, Abdullah Z, Schildberg FA, Odenthal M, Dienes HP, van Rooijen N, Schmitt E, Garbi N, Croft M, Kurts C, Kubes P, Protzer U, Heikenwalder M, Knolle PA. Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection. Nat Immunol 2013;14(6):574-83. doi: 10.1038/ni.2573. Epub 2013 Apr 14.
Welz M, Eickhoff S, Abdullah Z, Trebicka J, Gartlan KH, Spicer JA, Demetris AJ, Akhlaghi H, Anton M, Manske K, Zehn D, Nieswandt B, Kurts C, Trapani JA, Knolle P, Wohlleber D, Kastenmüller W. Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis. Nat Commun 2018;9(1):4805. doi: 10.1038/s41467-018-07213-x.
Baumann T, Dunkel A, Schmid C, Schmitt S, Hiltensperger M, Lohr K, Laketa V, Donakonda S, Ahting U, Lorenz-Depiereux B, Heil JE, Schredelseker J, Simeoni L, Fecher C, Körber N, Bauer T, Hüser N, Hartmann D, Laschinger M, Eyerich K, Eyerich S, Anton M, Streeter M, Wang T, Schraven B, Spiegel D, Assaad F, Misgeld T, Zischka H, Murray PJ, Heine A, Heikenwälder M, Korn T, Dawid C, Hofmann T, Knolle PA, Höchst B. Regulatory myeloid cells paralyze T cells through cell-cell transfer of the metabolite methylglyoxal. Nat Immunol 2020;21(5):555-566. doi: 10.1038/s41590-020-0666-9. Epub 2020 Apr 23.
Hackstein CP, Assmus LM, Welz M, Klein S, Schwandt T, Schultze J, Förster I, Gondorf F, Beyer M, Kroy D, Kurts C, Trebicka J, Kastenmüller W, Knolle PA, Abdullah Z. Gut microbial translocation corrupts myeloid cell function to control bacterial infection during liver cirrhosis. Gut 2017;66(3):507-518. doi: 10.1136/gutjnl-2015-311224. Epub 2016 Jul 18.
Manske K, Kallin N, König V, Schneider A, Kurz S, Bosch M, Welz M, Cheng RL, Bengsch B, Steiger K, Protzer U, Thimme R, Knolle PA, Wohlleber D. Outcome of Antiviral Immunity in the Liver Is Shaped by the Level of Antigen Expressed in Infected Hepatocytes. Hepatology 2018;68(6):2089-2105. doi: 10.1002/hep.30080. Epub 2018 Sep 27.
Schneider A, Kurz S, Manske K, Janas M, Heikenwälder M, Misgeld T, Aichler M, Weissmann SF, Zischka H, Knolle P, Wohlleber D. Single organelle analysis to characterize mitochondrial function and crosstalk during viral infection. Sci Rep 2019;9(1):8492. doi: 10.1038/s41598-019-44922-9.
Lampl S, Janas MK, Donakonda S, Brugger M, Lohr K, Schneider A, Manske K, Sperl LE, Kläger S, Küster B, Wettmarshausen J, Müller C, Laschinger M, Hartmann D, Hüser N, Perocchi F, Schmitt-Kopplin P, Hagn F, Zender L, Hornung V, Borner C, Pichlmair A, Kashkar H, Klingenspor M, Prinz M, Schreiner S, Conrad M, Jost PJ, Zischka H, Steiger K, Krönke M, Zehn D, Protzer U, Heikenwälder M, Knolle PA, Wohlleber D. Reduced mitochondrial resilience enables non-canonical induction of apoptosis after TNF receptor signalling in virus-infected hepatocytes. J Hepatol 2020;73(6):1347-1359. doi: 10.1016/j.jhep.2020.06.026. Epub 2020 Jun 26.
Dudek M, Pfister D, Donakonda S, Filpe P, Schneider A, Laschinger M, Hartmann D, Hüser N, Meiser P, Bayerl F, Inverso D, Wigger J, Sebode M, Öllinger R, Rad R, Hegenbarth S, Anton M, Guillot A, Bowman A, Heide D, Müller F, Ramadori P, Leone V, Garcia-Caceres C, Gruber T, Seifert G, Kabat AM, Mallm JP, Reider S, Effenberger M, Roth S, Billeter AT, Müller-Stich B, Pearce EJ, Koch-Nolte F, Käser R, Tilg H, Thimme R, Boettler T, Tacke F, Dufour JF, Haller D, Murray PJ, Heeren R, Zehn D, Böttcher JP, Heikenwälder M, Knolle PA. Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH. Nature 2021;592(7854):444-449. doi: 10.1038/s41586-021-03233-8. Epub 2021 Mar 24.