The role of innate lymphoid cells in liver disease

Abstract

Innate lymphoid cells (ILCs) are a family of innate immune cells that mirror the functionality of T lymphocytes but do not express rearranged antigen receptors. As tissue-resident cells, ILCs primarily reside in peripheral organs and at mucosal surfaces where they engage in local immune responses as well as in homeostatic or metabolic processes. Accumulating evidence indicates that ILCs are critically involved in numerous inflammatory diseases affecting various tissues of the body. However, data on the composition and biological function of human liver-resident ILCs and their role in liver fibrosis are scarce and published studies have reported conflicting results. <br /> The work in this thesis aimed to significantly improve our current knowledge by providing a detailed characterisation of the human intrahepatic ILC pool and by further assessing its involvement in hepatic fibrogenesis. For this purpose, tissue-resident ILCs were isolated from non-fibrotic and fibrotic or cirrhotic livers and analyzed using proteomic, transcriptional as well as functional assays. For comparative analyses, ILCs isolated from tonsillar and colon tissue, as well as from peripheral blood were additionally included in this project. <br /> Intrahepatic ILC3, which are currently considered to mainly comprise immature ILC precursors, were found to display a liver-specific capacity to produce the ILC2-specific cytokine IL-13. Given their considerably high proportion among intrahepatic ILCs, they in fact constitute the major IL-13-producing ILC subset in the human liver. Fibrotic or cirrhotic liver samples were characterized by an accumulation of this cell type which correlated with disease severity. Mechanistically, both IL-13 and stimulated liver ILC3 induced a pro-inflammatory profile in hepatic stellate cells, revealing a modulatory impact of tissue-resident ILCs on one of the major profibrogenic cell types in liver fibrosis. Studies of ILC plasticity identified liver-specifically enriched KLRG1-expressing ILC precursors to acquire a similar molecular phenotype under ILC3-priming conditions, thereby constituting the putative progenitor of IL-13-expressing liver ILC3. In summary, this study provides the first description of a so far unrecognized subset of IL-13+ ILC3 in the human liver, indicating that the pool of intrahepatic IL-13-producing ILCs is drastically underestimated up to date. The first evidence on their involvement in hepatic fibrogenesis and on their developmental trajectory might make a small but significant contribution to a better understanding of the biological role of human ILCs in the liver.