Heidelberg University, Medical Faculty Mannheim

Evaluation of Innate Lymphoid Cell subsets and AhR-signaling in mouse models of liver damage and regeneration

Liver possesses a remarkable capacity to regenerate after surgical removal or after chemical and mechanical damage. A better understanding of the immunological mechanisms driving liver damage and subsequent regeneration could help to design improved treatments for liver diseases. Within the past years, innate lymphoid cells (ILCs) were uncovered as important players in regulation of tissue homeostasis and immune responses within tissues. In the liver, group 1 ILCs, characterized by ability to produce IFN-γ, is the most abundant liver ILC subset. Liver ILC1 comprise conventional cytolytic NK cells (cNK) and tissue resident ILC1s that, in addition to IFN-γ, produce TNF-α and GM-CSF. Both subsets express the prototypic NK cell markers NK1.1 and NKp46, but originate from different precursors and show differential transcription factor requirement for their development. Liver NK1.1+ cells were shown to induce liver damage, but also to promote tissue regeneration e.g. by the activation of liver progenitor cells/oval cells. However, our understanding of i) the contribution of different ILC subsets to liver damage and regeneration ii) their plasticity during liver disease iii) their interaction with other immune and non-immune cells and iv) their sensing of and response to factors present in the liver microenvironment, is still incomplete. In our project, we aim to i) to further phenotypically and functionally dissect liver ILC1 subsets during liver damage and regeneration using both acute and chronic animal models of damage, ii) to determine ILC1 interactions with other immune cells within the liver microenvironment and iii) to evaluate the contribution of signaling via the  Aryl Hydrocarbon Receptor (AhR) that detects different exogenous and endogenous ligands to their responses. Our results will determine to which extent and by which mechanisms ILC1 subsets orchestrate liver damage and liver regeneration. Our experiments are designed to increase our basic knowledge of ILC biology in the liver, with potential implications for ILCs residing in other organs, and might reveal ILCs as novel targets for the treatment of liver diseases.