Liver . Fibrosis . Fatty Liver Disease . Autoimmune Liver Diseases Mucosal-associated Invariant T (MAIT) Cells . MHC-related Protein MR1
Characterization of mucosal-associated invariant T cells in liver diseases
Accumulating evidence suggests that the gut microbiome (i.e. gut resident bacteria)is involved in the pathogenesis of various liver diseases. Interestingly, a specialized T cell subset belonging to the family of innate-like lymphocytes is highly abundant both in the gut mucosa and the liver. These mucosal-associated invariantT (MAIT) cells respond to bacterial metabolites produced in the vitamin B2 (riboflavin) synthesis pathway, what places them at a central position in the immunological gut-liver axis. Antigen presentation to MAIT cells involves the highly conserved MHC-related protein MR1. Since these MR1-restricted T cells were identified in the liver only recently, little is known about their function in healthy and diseased liver.
Our aim is to elucidate the role of MAIT cells in selected liver diseases, including autoimmune liver diseases, steato hepatitis and viral hepatitis, and in the fibrogenic response in the liver. Our studies address a largely unexplored area of human liver physiology and pathology. Due to their location and high abundance in the liver, and their responsiveness to bacterial products and various cytokines, we hypothesize that liver-resident MAIT cells play a role in the pathogenesis of liver diseases and that changes in MAIT abundance, activation status, and cytokine expression profile influence disease development and outcome.
Our study has three main goals:
- To characterize liver-resident MAIT cells using patient-derived liver biopsies and blood samples. Using both cellular and molecular approaches, we are determining MAIT cell location and abundance in the liver and blood in different pathological conditions, and analyzing their functional and transcriptional profiles.
- To determine how the gut microbiome influences MAIT cells present in the liver,gut, and blood. By analyzing tissue and stool samples from patients with liver diseases, we aim at establishing whether changes in bacterial composition parallel changes in the functionality of MAIT cells.
- To identify and characterize interactions of MAIT cells within the liver environment.In cell culture experiments, performed with distinct purified subpopulations of primary human liver cells, we are defining the cellular and cytokine milieu contributing to MAIT cell activation.
The anticipated outcome of our experiments is identification of disease-specific changes and patterns that will allow us to draw conclusions about how MAIT cells influence liver physiology and pathology.