Deciphering the role of CNS-infiltrating MAIT cells in autoimmune CNS inflammation

• Applicant: Dr. Anne Willing
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases
• Term: from 2021 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 470154978

Multiple sclerosis (MS), the most common inflammatory disease of the central nervous system (CNS), is characterized by CNS infiltrating T cells. Although their specificity and function remain largely unknown, interleukin (IL)-17 producing T cells are enriched in active MS lesions. The vast majority of IL-17-producing CD8 T cells belong to the mucosal-associated invariant T (MAIT) cells, which recognize a new class of antigen, derivatives of vitamin B2 metabolites produced by bacteria and yeast, which are presented by major histocompatibility complex (MHC)-related protein 1 (MR1). Indeed, we could previously identify MAIT cells in MS brain lesions and found them to be reduced in their frequency and to produce increased amounts of IL-17 in the peripheral blood of MS patients. Regulatory as well as pro-inflammatory functions have been proposed for MAIT cells in MS pathogenesis. Though, in humans, causality is difficult to infer and mechanisms are challenging to address. MR1-tetramers for specific identification of MAIT cells in mice are only available since 2016. Using them in experimental autoimmune encephalomyelitis (EAE), the mouse model of MS, we found a strong enrichment of activated, IL-17-producing MAIT cells in the CNS. However, despite their pro-inflammatory cytokine profile, our preliminary data implicate a protective effect of T cell receptor (TCR)-mediated MAIT cell activation in vivo in the EAE model. Recent reports have for the first time described tissue repair function of MAIT cells after TCR-mediated activation, but this has so far not been described in autoimmune diseases. Indeed, we detected upregulated tissue repair gene expression signatures in CNS-infiltrating MAIT cells by RNA sequencing. Here we aim at investigating the link between TCR-mediated activation and tissue repair function of MAIT cells in EAE. We will proof and quantify TCR mediated activation of MAIT cells and decipher its influence on the disease course with different approaches including blockade and genetic ablation of MR1. Finally, we will investigate cellular and molecular mechanisms that potentially mediate tissue repair function of MAIT cells in EAE. Establishing a link between TCR-mediated activation and tissue repair function by MAIT cells in EAE would render them an accessible target for intervention in MS.

• DFG Programme: Research Grants