Regulation of mucosal-associated invariant T (MAIT) cell activation and function by metabolic reprogramming

• Applicant: Katrin Böttcher, Ph.D.
• Subject Area: Gastroenterology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 424774790

Chronic liver diseases and their complications affect a large population worldwide and represent a major health burden. They can develop from various stimuli, although inflammation is considered as a key disease driver, regardless of the aetiology. Mucosal-associated invariant T (MAIT) cells, a population of innate-like T cells particularly enriched in the liver, are important mediators of hepatic inflammation. Recognising bacterial-derived antigen, they contribute to anti-microbial defence. However, their innate-like nature allows for antigen-independent activation by pro-inflammatory cytokines, rendering them capable of orchestrating sterile inflammation. We have identified activated MAIT cells as mediators of liver fibrosis development in chronic liver disease, such as autoimmune liver disease and non-alcoholic fatty liver disease (NAFLD). Thus, the pro-inflammatory cytokine IL-12 serves as an activator of IL-17 expression by MAIT cells. Such IL-17 is able to induce hepatic stellate cell activation, a process central to the development of hepatic fibrosis.Current research has identified immune cell metabolism as a crucial regulator of immune cell function, since the metabolic needs of immune cells fundamentally change upon activation, when resting, naïve immune cells develop into specialised effector cells. It remains however unknown whether MAIT cell activation and function depends on metabolic reprogramming. The current proposal aims at investigating the importance of metabolic reprogramming for MAIT cell activation and function in order to identify molecular targets for the modulation of MAIT cell function. NAFLD affects more than 20% of the adult population worldwide, thus becoming the most common liver disease. The pathogenesis of NAFLD is complex and not fully understood, wherefore effective therapeutic strategies are lacking. Currently, hepatic lipid accumulation, metabolic dysfunction and inflammation are considered as main pathogenic drivers in NAFLD. Therefore, we will investigate whether MAIT cell metabolism and function is altered in patients with NAFLD. Moreover, we will analyse the interaction between the altered metabolic environment in NAFLD and MAIT cell metabolism and function, as well as the role of MAIT cells as pathogenic disease drivers of NAFLD and its complications. Our research is aiming at identifying novel molecular pathways that will help to understand the pathogenesis of NAFLD better and facilitate the development of novel therapeutic strategies.

• DFG Programme: Research Grants
• International Connection: United Kingdom
• Cooperation Partners: Professor Dr. Massimo Pinzani; Dr. Emmanouil Tsochatzis