EN
Project - A01:
Autoaggressive CD4+ T cells participate in autoimmune liver disease
Project leader:
Nicola Gagliani; Prof. Ph.D.
Summary
Autoaggressive T cells have been proposed to play a pathological role in the liver. However, whether this also applies to autoimmune liver diseases, e.g., autoimmune hepatitis (AIH), is still unclear, especially regarding CD4+ T cells. AIH is a prototypical autoimmune disease characterised by lymphocyte aggres-sion, most likely towards self-antigen on hepatocytes. However, intestinal microbiota dysbiosis has also been suggested to be associated to this disease. The central hypothesis of this project is that liver-infiltrating autoaggressive CD4+ T cells are microbiota-specific but, contribute to the development of AIH when they are aberrantly activated in an antigen-independent manner. Importantly, being part of this consortium will help to contrast and compare the function of autoaggressive CD4+ T cells between AIH and other liver diseases, such as PSC, and thus define disease-specific, but also common immunological principles of inflammation and immune regulation in the liver. Long-term aims are i) to identify specific targets for the pathogenic liver autoaggressive CD4+ T cells in order to selectively deplete them, and ii) to take advantage of T cell plasticity to reconvert autoaggressive CD4+ T cells into anti-inflammatory cells. We have already shown that it is possible to convert potentially pathogenic CD4+ T cells into anti-inflammatory IL-10-producing cells and, in parallel, it has been shown that IL-10-producing T cells can re-establish tolerance in a mouse model of liver inflammation.
Project plan
Our central hypothesis is that some of the liver CD4+ T cells acquire an autoaggressive function and contribute to the development of AIH. We aim to understand whether some of the liver CD4+ T cells develop in response to intestinal microbiota. In addition, we aim to test whether this response epigenetically predisposes these cells to contribute to AIH by acquiring an auto-aggressive function when activated in an antigen-independent way by proinflammatory cytokines. We suggest that, once aberrantly activated, these autoaggressive liver CD4+ T cells either directly or indirectly, by activating other immune cells, lead to liver damage typically observed in AIH (Graphical abstract of the hypothesis).
In order to test this hypothesis, our work programme has the following work packages (WP):
WP1: To identify antigen specificity and activation mechanisms of autoaggressive CD4+ T cells in AIH.
WP2: To test the function of CD4+ Trm cells in mouse models of liver diseases.
Project related publications
Amezcua Vesely MC, Pallis P, Bielecki P, Low JS, Zhao J, Harman CCD, Kroehling L, Jackson R, Bailis W, Licona-Limon P, Xu H, Iijima N, Pillai PS, Kaplan DH, Weaver CT, Kluger Y, Kowalczyk MS, Iwasaki A, Pereira JP, Esplugues E, Gagliani N#, Flavell RA#. Effector T(H)17 Cells Give Rise to Long-Lived T(RM) Cells that Are Essential for an Immediate Response against Bacterial Infection. Cell 2019;178:1176-1188.e15. doi: 10.1016/j.cell.2019.07.032. Open access.
Zhao Y, Kilian C, Turner JE, Bosurgi L, Roedl K, Bartsch P, Gnirck AC, Cortesi F, Schultheiss C, Hellmig M, Enk LUB, Hausmann F, Borchers A, Wong MN, Paust HJ, Siracusa F, Scheibel N, Herrmann M, Rosati E, Bacher P, Kylies D, Jarczak D, Lutgehetmann M, Pfefferle S, Steurer S, S. Zur-Wiesch J,. Puelles VG, Sperhake JP, Addo MM, Lohse AW, Binder M, Huber S, Huber TB, Kluge S, Bonn S, Panzer U#, Gagliani N#, Krebs CF#. Clonal expansion and activation of tissue-resident memory-like Th17 cells expressing GM-CSF in the lungs of severe COVID-19 patients. Sci Immunol 2021;6:eabf6692. Open access.
Gagliani N, Amezcua Vesely MC, Iseppon A, Brockmann L, Xu H, Palm NW, de Zoete MR, Licona-Limon P, Paiva RS, Ching T, Weaver C, Zi X, Pan X, Fan R, Garmire LX, Cotton MJ, Drier Y, Bernstein B, Geginat J, Stockinger B, Esplugues E, Huber S#, Flavel RA#. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 2015;523:221-5. doi: 10.1038/nature14452. Epub 2015 Apr 29.
Xu H#, Agalioti T#, Zhao J, Steglich B, Wahib R, Vesely MCA, Bielecki P, Bailis W, Jackson R, Perez D, Izbicki J, Licona-Limon P, Kaartinen V, Geginat J, Esplugues E, Tolosa E, Huber S, Flavell RA#, Gagliani N#. The induction and function of the anti-inflammatory fate of T(H)17 cells. Nat Commun 2020;11:3334. doi: 10.1038/s41467-020-17097-5.Open access.
Agalioti T#, Villablanca EJ#, Huber S#, Gagliani N#. T(H)17 cell plasticity: The role of dendritic cells and molecular mechanisms. J Autoimmun 2018;87:50-60. doi: 10.1016/j.jaut.2017.12.003. Epub 2018 Jan 19.Open access.
Krebs CF, Reimers D, Zhao Y, Paust HJ, Bartsch P, Nunez S, Rosemblatt MV, Hellmig M, Kilian C, Borchers A, Enk LUB, Zinke M, Becker M, Schmid J, Klinge S, Wong MN, Puelles VG, Schmidt C, Bertram T, Stumpf N, Hoxha E, Meyer-Schwesinger C, Lindenmeyer MT, Cohen CD, Rink M, Kurts C, Franzenburg S, Koch-Nolte F, Turner JE, Riedel JH, Huber S, Gagliani N, Huber TB, Wiech T, Rohde H, Bono MR, Bonn S, Panzer U, Mittrucker HW. Pathogen-induced tissue-resident memory T(H)17 (T(RM)17) cells amplify autoimmune kidney disease. Sci Immunol 2020;5:eaba4163. doi: 10.1126/sciimmunol.aba4163.
Siracusa F, Schaltenberg N, Kumar Y, Lesker TR, Steglich B, Liwinski T, Cortesi F, Frommann L, Diercks BP, Bonisch F, Fischer AW, Scognamiglio P, Pauly MJ, Casar C, Cohen Y, Pelczar P, Agalioti T, Delfs F, Worthmann A, Wahib R, Jagemann B, Mittrucker HW, Kretz O, Guse AH, Izbicki JR, Lassen KG, Strowig T, Schweizer M, Villablanca EJ, Elinav E, Huber S, Heeren J, Gagliani N. Short-term dietary changes can result in mucosal and systemic immune depression. Nat Immunol 2023;24:1473-1486. doi: 10.1038/s41590-023-01587-x. Epub 2023 Aug 14.
Tintelnot J, Xu Y, Lesker TR, Schonlein M, Konczalla L, Giannou AD, Pelczar P, Kylies D, Puelles VG, Bielecka AA, Peschka M, Cortesi F, Riecken K, Jung M, Amend L, Broring TS, Trajkovic-Arsic M, Siveke JT, Renne T, Zhang D, Boeck S, Strowig T, Uzunoglu FG, Gungor C, Stein A, Izbicki JR, Bokemeyer C, Sinn M, Kimmelman AC, Huber S#, Gagliani N#.. Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. Nature 2023;615:168-174. doi: 10.1038/s41586-023-05728-y. Epub 2023 Feb 22.Open access.
Poch T, Krause J, Casar C, Liwinski T, Glau L, Kaufmann M, Ahrenstorf AE, Hess LU, Ziegler AE, Martrus G, Lunemann S, Sebode M, Li J, Schwinge D, Krebs CF, Franke A, Friese MA, Oldhafer KJ, Fischer L, Altfeld M, Lohse AW, Huber S, Tolosa E#, Gagliani N#, Schramm C#. Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4(+) T cells in primary sclerosing cholangitis. J Hepatol 2021;75:414-423. doi: 10.1016/j.jhep.2021.03.016. Epub 2021 Mar 24.Open access.
Woestemeier A, Scognamiglio P, Zhao Y, Wagner J, Muscate F, Casar C, Siracusa F, Cortesi F, Agalioti T, Muller S, Sagebiel A, Konczalla L, Wahib R, Karstens KF, Giannou AD, Dupree A, Wolter S, Wong MN, Muhlig AK, Bielecka AA, Bansal V, Zhang T, Mann O, Puelles VG, Huber TB, Lohse AW, Izbicki JR, Palm NW, Bonn S, Huber S, Gagliani N. Multicytokine-producing CD4+ T cells characterize the livers of patients with NASH. JCI Insight 2023;8(1):e153831. doi: 10.1172/jci.insight.153831. Open access.
# equal contribution