Role of the Interleukin-2 pathways in hepatic innate lymphoid cells during steady state, fibrosis and hepatocellular carcinoma
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Abstract
The immune system is an essential part of our body that is able to combat diverse
attacks like viruses, bacteria and tumor cells. At the same time it needs a tight
regulation as an overwhelming immune response can harm healthy cells and organs
whereas an improper immune response can lead to the spread of invading pathogens
within the body. Cytokines are able to regulate immune responses. One of them,
namely interleukin- (IL)2, is mainly secreted by cluster of differentiation (CD)4 T cells
and consumed by regulatory T cells (Tregs), both cell compartments of the adaptive
immune system (Gordon et al., 1965). It was just recently described that IL2 can also
act on cells of the innate immune system, mainly group 1 innate lymphoid cells (ILCs)
(Gasteiger, Hemmers, Bos, et al., 2013; Gasteiger, Hemmers, Firth, et al., 2013). The
exact role of IL2 on group 1 ILCs still remains largely unknown. The aim of this thesis
was to establish mainly flow cytometric methods to study hepatic immune cells,
herewith especially group 1 ILCs, in the course of diet- and toxin-driven liver disease
models. Additionally, the role of group 1 ILCs within these models should be
characterized with the help of genetic mouse models. IL2 and its receptor subunit
CD25 were studied in regard of their potential to regulate the group 1 ILC-mediated
immune response in conditional knockout mice. It can be shown that in different longterm
models of liver fibrosis ILC1s upregulated CD25. Models investigated are cholinedeficient
high-fat diet (CD-HFD), high-fat high-carb (HFHC) diet and carbon
tetrachloride (CCl4)- and thioacetamide (TAA)-induced liver fibrosis. We performed
these experiments with wildtype (WT) mice and genetic knockouts (KOs) specifically
depleting either IL2 or CD25 in natural killer (NK)p46+ group 1 ILCs. Group 1 ILCs
showed a higher proliferation after long-term CD-HFD and at the same time produced
less cytokines like interferon gamma (IFNg), IL2 and tumor necrosis factor alpha
(TNFa). Unexpectedly, depletion of group 1 ILCs led to reduced inflammation and
increased anti-inflammatory M2-like macrophages (MPs) during CD-HFD and an
increase in M2-like MPs, granulocyte (Gr)1+ cells and DCs in the reversal phase of
CCl4-induced liver fibrosis. Depletion of CD25 in group 1 ILCs led to a slight increase
in IL2 production from ILC1s whereas the overall production of IL2 by ILC1s
tremendously decreased after CCl4-induced liver fibrosis. Therefore, IL2-depletion on
group 1 ILCs seems to affect mainly the innate immune cell compartment. M2-like MPs
increase during the acute phase of CCl4-induced liver fibrosis whereas M1-like MPs
increase during the reversal phase. Further experiments focused on the role of matrix
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metalloproteases (MMPs) for ILC1 function. MMP3 KO mice showed altered
proliferation and CD25 expression of ILC1s during the acute and reversal phase of
CCl4-induced liver fibrosis. In summary, the presented work highlights diverse roles of
ILC1s and ILC-derived IL2 during the acute phase of liver fibrosis and in the tissue
healing phase.