B1 - Regulation of immune-mediated liver injury
Prof. Dr. rer. nat. Gisa Tiegs
Department of Experimental Immunology and Hepatology
University Medical Center Hamburg-Eppendorf
PD Dr. rer. nat. Andrea Kristina Horst
Institut für Experimentelle Immunologie und Hepatologie
Elena Tasika – MTA
Dr. Birgit Schiller – PostDoc
Mareike Kellerer – PhD student
The liver as a tolerogenic organ is constantly challenged by microbial and food antigens. Hence, liver tolerance is modulated by the gut microbiota and their metabolites which lead induce immune regulatory T cells (Tregs), depending on their composition. Treg induction and homeostasis is controlled by IL-2-signaling. Immune-checkpoint regulators, such as CEACAM1, affect IL-2-mediated signaling pathways; the anti-inflammatory properties of Tregs are mediated in part by IL-10 secretion.
Inflammatory and autoimmune liver disease emerge by inappropriate immune regulation and loss of tolerance. Loss of tolerance is propagated by a progressive dysbalance in pro-inflammatory and regulatory T cells. Hence, identification of novel mechanisms in immune regulation or immune-checkpoint inhibitors in cell-bound or soluble and/ or by particular components of the microbiome offers novel routes to therapy development.
The aim of this project is to decipher novel mechanisms of immune regulation and tolerance induction in response to liver injury. During the first funding period, we demonstrated in a mouse model for CD4+ T cell-dependent liver injury provoked by Concanavalin A (ConA) injection that tolerance induction after repeated ConA exposure depends on IL-10-producing, CXCR3+Tbet+ Tregs. Furthermore, we showed that hepatocytes and liver-resident endothelial cells (LSECs) as non-professional antigen-presenting cells in the liver, participate in the generation of IL-10-producing Tregs and that they interfere with pathways of T cell activation. In the current funding period, we will determine the role of the gut microbiota for the induction of IL-10-producing Tregs in the liver.
We will identify soluble factors produced by commensal microbes which are implicated in liver inflammation and tolerance induction. Bacterial metabolites, such as short-chain fatty acids are candidate substances involved in the regulation of liver tolerance. Additionally, we will address the role of the membrane-bound and soluble form of the microbial receptor and immune-checkpoint regulator CEACAM1 in T cell activation and antigen-presentation by intrahepatic, non-professional antigen-presenting cells. Our current publications show that CEACAM1 stimulates signaling via the IL-2 receptor and thus controls Treg induction in the liver (Hepatology, 2018).
Horst AK, Wegscheid C, Schaefers C, Schiller B, Neumann K, Lunemann S, Langeneckert AE, Oldhafer KJ, Weiler-Normann C, Lang KS, Singer BB, Altfeld M, Diehl L, Tiegs G.
Carcinoembryonic antigen-related cell adhesion molecule 1controls IL-2-dependent regulatory T-cell induction in immune-mediated hepatitis in mice.
Hepatology. 2018 Jan 29. doi: 10.1002/hep.29812. [Epub ahead of print]
Neumann K, Karimi K, Meiners J, Voetlause R, Steinmann S, Dammermann W, Lüth S, Asghari F, Wegscheid C, Horst AK, Tiegs G
A Proinflammatory Role of Type 2 Innate Lymphoid Cells in Murine Immune-Mediated Hepatitis
J Immunol. 2017 Jan 1;198(1):128-137.
Horst AK, Neumann K, Diehl L, Tiegs G
Modulation of liver tolerance by conventional and nonconventional antigen-presenting cells and regulatory immune cells
Cell Mol Immunol. 2016 May;13(3):277-92. doi: 10.1038/cmi.2015.112. Epub 2016 Apr 4. Review