MAIT cells: not just another brick in the wall.

The link between gut and joint inflammation in spondyloarthritis (SpA) is well established, in particular in ankylosing spondylitis (AS) and peripheral SpA. In 1995, Mielants et al discovered that almost 50% of patients with SpA have subclinical gut inflammation, of which a fraction develops Crohn’s disease over time. Recent studies clearly showed that the onset of disease and disease severity are linked to the presence of subclinical gut inflammation. However, the mechanism behind this phenomenon is hitherto not fully elucidated. Over the past decade, the interleukin (IL)-23/IL-17-axis has been put forward as a key player in the pathogenesis of SpA. Polymorphisms in the IL23R gene were found both in SpA and in inflammatory bowel disease (IBD), linking pathology in these physically distant sites. Cells that are typically responsive to IL-23 are IL-23RRORγt IL-17A-producing cells, such as TH17 cells. In multiple inflammatory diseases, such as multiple sclerosis (MS), IBD and SpA, it is assumed that there is an overall distortion of the cytokine profile towards IL-17A, contributing to disease. However, it should be noted that in IBD IL-17A might also exert tissue-protective functions and that mechanisms driving gut inflammation in SpA do not necessarily represent those contributing to the development of full-blown IBD. Intriguingly, Sherlock et al showed that systemic IL-23 overexpression is able to drive the development of enthesitis via enthesis-resident CD3CD4CD8RORγtIL23R T cells, independently of TH17 cells. The concept that not TH17 cells but innate-like T cells such as γδ Tcells, invariant natural killer T cells (iNKT) and mucosal-associated invariant T (MAIT) cells are the main source of IL-17A recently gained support. Interestingly, innate-like T cells such as MAIT cells act at the intersection of the innate and adaptive immune systems. They rapidly produce cytokines with a TH1 (tumour necrosis factor (TNF) and interferon-gamma (IFNγ)) or TH17 (IL-17A) profile upon T cell receptor (TCR)-dependent and TCR-independent signals. It is, thus, obvious that the activation of such potent cells incurs risks. Hence, multiple reports describe the involvement of MAIT cells in inflammatory diseases such as MS, IBD and rheumatoid arthritis (RA). MR1 mice, which lack MAIT cells, had reduced severity of antibody-induced arthritis and collagen-induced arthritis, both models for RA, suggesting a pathological role for MAIT cells in RA. In this issue of Annals of the Rheumatic diseases, Gracey et al are the first to investigate the number of MAIT cells and their functional phenotype in patients with AS. As in many other inflammatory diseases, they report a relative abundance of IL-17-producing MAIT cells in patients with AS, both systemically and in synovial fluid compared with healthy controls and patients with RA. However, it still needs to be elucidated to what extent these cells are developmentally programmed to attain this IL-17A-producing phenotype or if they acquire these characteristics in the periphery under inflammatory conditions after being fully matured. Furthermore, it should be noted that the majority of MAIT cells (80–90%) produce TNF and IFNγ compared with approximately 3% IL-17A-producing MAIT cells. Despite their overall low numbers, they might still be critical in driving disease as their numbers are heightened both systemically and in synovial fluid of patients with AS compared with healthy controls and patients with RA. A key question is whether these cells can be modulated under inflammatory conditions towards a tissue-protective phenotype. Modulation of MAIT cells might be a more interesting therapeutic approach than modulation of their phenotypical and functional counterparts, the iNKT cells. MAIT cell numbers are relatively high in humans (1–10% of circulating T cells, 20–45% of T cells in the liver and 3–5% of lymphoid cells in the intestinal mucosa), compared with numbers of iNKT cells. The opposite situation is present in mice, where iNKT cells are rather abundant compared with MAIT cells, the latter also not displaying a functionally mature phenotype as can be found in humans. This bias might suggest an evolutionary need for one or the other cell type. In many inflammatory diseases, systemic MAIT cell numbers are lowered compared with healthy controls, with a relative enrichment in the inflamed tissues. 7 A similar situation was found in patients with AS and patients with RA, where MAIT cells were enriched in the synovial fluid and lowered systemically. Even though the numbers between AS and RA seem comparable, they phenotypically differ as only in patients with AS MAIT cells had a predominant IL-17A profile. Human MAIT cells are often characterised as CD3 TCRVα7.2 CD161 T cells. 12 The use of this marker panel is, however, not without any risks, especially when used to characterise MAIT cells in patients suffering from inflammatory diseases. Upon activation, MAIT cells downregulate CD161 and the expression of this marker can be confounded by the use of corticosteroids. In axial SpA and, to a lesser extent, peripheral SpA, corticosteroids are not the therapy of choice and decreases in MAIT cell frequencies due to corticosteroid use are not to be expected. The results described by Gracey et al come from a cross-sectional observational cohort, providing very useful insight into MAIT cell functionality in AS. However, the patients have been exposed to a wide variety of treatment strategies, possibly influencing data outcome. It would thus be interesting to see if similar results could be obtained in patients with newonset, therapy-naïve SpA. What makes MAIT cells an even more appealing cell type in the light of combined gut–joint disease, is that they typically reside in the epithelium and lamina propria of the gut, a site of important host–microbial interplay. Here, they fully mature after thymic emigration, a process that depends on the presence of the commensal microbial flora and B cells. A hallmark of these cells is their highly restricted TCR Vα repertoire. They react to non-peptide antigens, bound by the non-classical class I antigenpresenting molecule, MR1 that is highly conserved across mammalian species (figure 1). MR1 presents vitamin B2 metabolites, which are specific to certain species of the microbiota such as Salmonella enterica serovar Typhimurium, to MAIT cells. 12 However, the exact set of antigens recognised by MAIT cells is Department of Internal Medicine—Rheumatology, Ghent University, Ghent, Belgium; Unit of Molecular Immunology and Inflammation, Inflammation Research Center—VIB, Ghent, Belgium; KU Leuven and Division of Rheumatology, Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, University Hospitals Leuven, Leuven, Belgium