Mucosal-associated invariant T (MAIT) cells in the pathogenesis of central nervous system inflammation

Abstract

Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system (CNS) affecting approximately 2.5 million people worldwide, whereas no curative treatment exists. The complex contribution of immune cells to damage and repair of the CNS in MS pathogenesis is unresolved and a major focus of MS research. MS is considered to be an autoimmune disease most likely caused by autoreactive T cells. A recently discovered T cell population, mucosal-associated invariant T (MAIT) cells, is highly abundant in humans and shares many similarities with T helper 17 (Th17) cells, a T cell subset previously implicated to play a fundamental role in MS and its animal model experimental autoimmune encephalomyelitis (EAE). Indeed, MAIT cells have been detected in inflamed brain lesions of MS patients. However, functional analyses of CNS-infiltrating MAIT cells are lacking and require a characterisation in the EAE model. In this work, newly available tools to study MAIT cells in mice were combined with the EAE model enabling for the first time to characterise CNS-infiltrating MAIT cells in EAE and to investigate their role in EAE pathogenesis. Few MAIT cells were found in the CNS of naïve mice, whereas MAIT cells highly accumulated in the CNS of mice with EAE. The substantial increase of MAIT cell frequencies in the CNS already during preclinical EAE as well as the upregulation of chemokine receptor and integrin expression by CNS-infiltrating MAIT cells indicated CNS infiltration of MAIT cells from the periphery, while a local proliferation of CNS-resident MAIT cells could not be excluded. Transcriptome analysis and the use of Nur77GFP reporter mice revealed that MAIT cells in the inflamed CNS were activated by cytokines and antigen-specifically via their TCR. Published studies recently showed that TCR-dependent activation of MAIT cells induced a tissue repair function, while cytokine-dependent activated upregulated proinflammatory and cytotoxic molecules. In line with these studies of other disease models, proinflammatory and tissue repair signatures as well as RORγt+ T-bet+ or RORγt+ T-bet– MAIT cell subsets were identified in the inflamed CNS. MAIT cells in EAE closely resembled pathogenic Th17 cells and produced the cytokines GM-CSF, IL-17A and IFN-γ, which are known to contribute to EAE pathogenesis. However, analysing the EAE course of Mr1–/– mice and mice treated with an anti-MR1 antibody uncovered that the protective exceeded the proinflammatory effects of MAIT cells in EAE resulting in a more severe disease course. Using an anti-MR1 blocking antibody most likely avoided developmental phenotypes observed in Mr1–/– mice and blocked the TCR-dependent activation of MAIT cells required for the upregulation of the tissue repair signature. Specific molecules involved in MAIT cell mediated tissue repair remain elusive. Amphiregulin (AREG) might be a candidate for further investigations, since Areg was strongly upregulated in MAIT cells isolated from the CNS of mice in acute EAE and published studies uncovered a protective effect of AREG in a stroke mouse model and claimed a similar effect in EAE. In summary, this work proposes that differentially activated MAIT cells infiltrate the inflamed CNS and fulfil either proinflammatory or tissue repair function, while in vivo experiments indicates that the protective effect exceeds. Therefore, specifically inducing the tissue repair potential of MAIT cells and blocking their proinflammatory functions represent interesting treatment opportunities for MAIT cells in EAE and MS.