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Role of liver cells in bacterial antigen metabolism and MAIT cell activation

Lett, Martin. Role of liver cells in bacterial antigen metabolism and MAIT cell activation. 2021, Doctoral Thesis, University of Basel, Faculty of Science.

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Abstract

Background and rationale: Mucosal-associated invariant T (MAIT) cells are an evolutionary conserved subset of T cells with a partially invariant T cell receptor (TCR). The recent discovery of their antigen (Ag), and MR1 as the Ag-presenting molecule, demonstrated their microbial restriction and stimulated their study in humans. Changes in their phenotype have been observed in infectious and autoimmune diseases. Decreases in MAIT cell frequency have been observed in several chronic inflammatory diseases. These alterations are particularly observed in the liver, where MAIT cells represent the most abundant T cell population in healthy humans. Moreover, studies conducted in animal models showed a deleterious effect of activated MAIT cells in liver fibrosis. The process leading to MAIT cell activation remains largely unexplored, and only biliary cells have been shown to be able to present Ag to them in the liver environment. Here we assessed the activation of MAIT cells by various human primary liver cell types. We also investigated the capacity of liver cells to generate active Ag from bacteria-derived precursor, and studied the influence of molecular cell-cell interactions and MR1-inhibitors on MAIT cell activation.
Results: Primary human parenchymal and non-parenchymal cells efficiently present bacterial and synthetic Ag to MAIT cells. The comparison between the cells shows that hepatocytes are most efficient in inducing IFNγ secretion by MAIT cells. This effect is not mediated by IL-18, IL-12 or IL-23. Primary liver cells are capable of generating the active antigen 5-OP-RU from its precursor 5-A-RU. This is of interest regarding our in silico data which predict passive diffusion of both compounds with a better score for 5-A-RU, the precursor. Liver cell-mediated MAIT cell activation is seen both in a MAIT cell clone derived from peripheral blood and in liver-derived MAIT cell lines, and leads to downregulation of the TCR, as well as IFNγ and IL-17A secretion. The incubation of primary liver cells with MR1 blocking ligands leads to a drastic diminution of the activation. I also identify CLEC2D as a potent regulator of MAIT cell activation, the surface over-expression of which is strongly inhibiting MAIT cell activation, as well as leading to CD161 downregulation.
Discussion: Considering the hypothesized role of activated MAIT cells in the vicious circle of liver fibrosis, the identification of their activation mechanism is decisive. We established that all tested primary liver cells are prone to present bacteria derived Ag to MAIT cells. Additionally, we observed that hepatocytes, the most abundant liver cells, are the most efficient ones, as seen by the more pronounced cytokine secretion they induced in MAIT cells. With such myriad of APCs surrounding them, the availability of MAIT cell antigen in the liver is critical. Our in silico model suggests that active Ag and precursor can reach the liver. This is of particular importance regarding our evidence that primary liver cells can generate active Ag from precursor. The deleterious action of activated MAIT cells in the liver argues for the study of approaches preventing their stimulation. We demonstrated that the use of MR1 blocking ligands was efficient in vitro, using primary human liver cells. Furthermore, our investigation of the mechanism behind the discordances of Ag presentation between liver cells lead us to consider the role of the ligand of CD161, CLEC2D. We demonstrated a CLEC2D dependent inhibition of IFNγ secretion associated with a downregulation of CD161 on MAIT cells. We do not know yet whether this mechanism explains the difference observed in Ag presentation. Nevertheless, these findings place CLEC2D as a new potential therapeutic target in immune regulation, especially in the liver, where the majority of T cells express CD161.
Overall, this work increases our understanding of MAIT cell activation in the human liver. The diffusion of MAIT cell Ag to the human liver has yet to be proven, but would argue for a central role of the intestinal microbiota and the integrity of the gut barrier in liver health. The study of the presence of MAIT cell stimulatory Ag in the circulation and liver in the liver disease context will help us understand better the pathophysiology of liver inflammatory diseases.
Advisors:Filipowicz Sinnreich, Magdalena
Committee Members:Hess, Christoph and Münz, Christian and Spiess, Martin
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Liver Immunology (Filipowicz Sinnreich)
UniBasel Contributors:Filipowicz Sinnreich, Magdalena and Hess, Christoph and Spiess, Martin
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14040
Thesis status:Complete
Number of Pages:200
Language:English
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss140406
edoc DOI:
Last Modified:11 May 2021 04:30
Deposited On:10 May 2021 13:52

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