Mucosal‐associated invariant T cells promote inflammation and exacerbate disease in murine models of arthritis

Chiba, Asako; Tajima, Ryohsuke; Tomi, Chiharu; Miyazaki, Yusei; Yamamura, Takashi; Miyake, Sachiko

doi:10.1002/art.33314

Cited by 114 publications

(97 citation statements)

References 45 publications

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“…The pro‐inflammatory cytokine IL‐17 is associated with SLE and correlated with disease activity,36, 37 whereas IL‐17‐producing T helper type 17 (Th17) cells are involved in driving local inflammation at sites of disease 38, 39. MAIT cells are potent producers of IL‐17 and due to their similar cytometric profile may in fact have constituted many of the ‘Th17’ populations measured in these studies 40. Local cytokine production by MAIT cells within tissues could contribute to lowering the quantitative threshold of immune signalling, a process believed to interact with genetic predispositions to contribute to the initial pathogenic processes in SLE 35.…”

Section: Observations From Specific Diseasesmentioning

confidence: 83%

“…Chiba et al 40. found that MR1 −/− mice, which lack MAIT cells, had reduced severity of CIA and of collagen antibody‐induced arthritis, whereas CIA was recapitulated by reconstitution with adoptively transferred MAIT cells.…”

Section: Observations From Specific Diseasesmentioning

confidence: 99%

“…3. Although our knowledge of the emerging field of MAIT cell biology is limited, several factors implicate these cells in immune‐mediated diseases, including their pro‐inflammatory profile,40 their widespread tissue distribution and effector‐memory phenotype. However, many clinical studies to date are confounded by the effect of therapeutic steroids, and others that use a V α 7.2CD161 + definition of MAIT cells may be confounded by the down‐regulation of CD161 which occurs with chronic activation 22, 85.…”

Section: Perspective and Future Directionsmentioning

confidence: 99%

“…Moreover, most clinical data are only observational, making it hard to determine whether aberrations are primary phenomena, or perhaps represent a response to the effects of a disordered cytokine milieu 35. Indeed, given their remarkable abundance and the potential for TCR‐independent activation of MAIT cells by cytokines such as IL‐12, IL‐18 and IL‐23, the most important effects of MAIT cells in autoimmunity could be non‐specific amplification of inflammatory cytokines leading to increased IFN‐ γ 41 and IL‐17 19, 40. Differences between murine models and human studies may be due to such confounding factors in human studies as well as differences between the species.…”

Section: Perspective and Future Directionsmentioning

confidence: 99%

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Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

2016

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SummaryMucosal‐associated invariant T (MAIT) cells are a novel class of innate‐like T cells, expressing a semi‐invariant T‐cell receptor (TCR) and able to recognize small molecules presented on the non‐polymorphic MHC‐related protein 1. Their intrinsic effector‐memory phenotype, enabling secretion of pro‐inflammatory cytokines, and their relative abundance in humans imply a significant potential to contribute to autoimmune processes. However, as MAIT cells were unknown until recently and specific immunological tools were unavailable, little is known of their roles in disease. Here I review observations from clinical studies and animal models of autoimmune and immune‐mediated diseases including the roles of MAIT cells in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and airways diseases. MAIT cell deficiencies are frequently observed in peripheral blood, and at sites of disease such as the airways in asthma. However, MAIT cells have a specific sensitivity to suppression by therapeutic corticosteroids that may confound many of these observations, as may the tendency of the surface marker CD161 to activation‐induced down‐regulation. Nonetheless, the dependence on bacteria for the development of MAIT cells suggests a potentially important protective role linking the influences of early life microbial exposures and subsequent development of autoimmunity. Conversely, MAIT cells could contribute to chronic inflammation either through TCR‐independent activation, or potentially by TCR recognition of as yet undiscovered ligands. Future research will be greatly facilitated by the immunological tools that are now available, including murine genetic models and human and murine specific tetramers.

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Section: Observations From Specific Diseasesmentioning

confidence: 83%

Section: Observations From Specific Diseasesmentioning

confidence: 99%

Section: Perspective and Future Directionsmentioning

confidence: 99%

Section: Perspective and Future Directionsmentioning

confidence: 99%

See 2 more Smart Citations

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

2016

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“…Furthermore, MAIT cells have been recently implicated to serve as regulatory and/or effector cells in patients with multiple sclerosis and murine model of arthritis (25,26). However, MAIT cell levels and functions have not previously been investigated in rheumatic diseases.…”

mentioning

confidence: 99%

Mucosal-Associated Invariant T Cell Deficiency in Systemic Lupus Erythematosus

Cho

Kee

Kim

et al. 2014

The Journal of Immunology

155

163

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Mucosal-associated invariant T (MAIT) cells contribute to protection against certain microorganism infections and play an important role in mucosal immunity. However, the role of MAIT cells remains enigmatic in autoimmune diseases. In this study, we examined the level and function of MAIT cells in patients with rheumatic diseases. MAIT cell, cytokine, and programmed death-1 (PD-1) levels were measured by flow cytometry. Circulating MAIT cell levels were significantly reduced in systemic lupus erythematosus (SLE) and rheumatoid arthritis patients. In particular, this MAIT cell deficiency was more prominent in CD8+ and double-negative T cell subsets, and significantly correlated with disease activity, such as SLE disease activity index and 28-joint disease activity score. Interestingly, MAIT cell frequency was significantly correlated with NKT cell frequency in SLE patients. IFN-γ production in MAIT cells was impaired in SLE patients, which was due to an intrinsic defect in the Ca2+/calcineurin/NFAT1 signaling pathway. In SLE patients, MAIT cells were poorly activated by α-galactosylceramide–stimulated NKT cells, thereby showing the dysfunction between MAIT cells and NKT cells. Notably, an elevated expression of PD-1 in MAIT cells and NKT cells was associated with SLE. In rheumatoid arthritis patients, MAIT cell levels were significantly higher in synovial fluid than in peripheral blood. Our study primarily demonstrates that MAIT cells are numerically and functionally deficient in SLE. In addition, we report a novel finding that this MAIT cell deficiency is associated with NKT cell deficiency and elevated PD-1 expression. These abnormalities possibly contribute to dysregulated mucosal immunity in SLE.

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Gut Inflammation in Axial Spondyloarthritis Patients is Characterized by a Marked Type 17 Skewed Mucosal Innate‐like T Cell Signature

Mortier

Quintelier

Craemer

et al. 2023

Arthritis & Rheumatology

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ObjectiveSpA patients often present with microscopic signs of gut inflammation, a risk factor for progressive disease. We investigated whether mucosal innate‐like T‐cells are involved in dysregulated interleukin (IL)‐23/IL‐17 responses in the gut‐joint axis in SpA.MethodsIleal and colonic intraepithelial lymphocytes (IEL) and lamina propria lymphocytes (LPL), and paired peripheral blood mononuclear cells (PBMC), were isolated from treatment‐naive non‐radiographic axial (nr‐ax)SpA patients with (n=11) and without (n=14) microscopic gut inflammation, and healthy controls (n=15), undergoing ileocolonoscopy. Presence of gut inflammation was assessed histopathologically. Immunophenotyping of innate‐like T‐cells and conventional T‐cells was performed using intracellular flow cytometry. Unsupervised clustering analysis was done by FlowSOM technology. Serum IL‐17A levels were measured via Luminex.ResultsMicroscopic gut inflammation in nr‐axSpA was characterized by increased ileal intraepithelial γδ‐hi‐T cells. γδ‐hi T cells were also increased in PBMC of nr‐axSpA patients versus healthy controls, and were strongly associated with ASDAS. The abundance of mucosal associated invariant T (MAIT)‐cells and invariant natural killer T (iNKT)‐cells was unaltered. Innate‐like T‐cells in the inflamed gut showed increased RORγt, IL‐17A and IL‐22 levels with loss of Tbet, a signature that was less pronounced in conventional T‐cells. Presence of gut inflammation was associated with higher serum IL‐17A levels. In patients treated with TNF blockade, the proportion of γδ‐hi cells and RORγt expression in blood was completely restored.ConclusionIntestinal innate‐like T‐cells display marked type 17 skewing in the inflamed gut mucosa of nr‐axSpA patients. γδ‐hi T cells are linked to intestinal inflammation and disease activity in SpA.This article is protected by copyright. All rights reserved.

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Mucosal‐associated invariant T cells promote inflammation and exacerbate disease in murine models of arthritis

Abstract: Conclusion. These results indicate that MAIT cells exacerbate arthritis by enhancing the inflammation.

Cited by 114 publications

References 45 publications

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

Mucosal-Associated Invariant T Cell Deficiency in Systemic Lupus Erythematosus

Gut Inflammation in Axial Spondyloarthritis Patients is Characterized by a Marked Type 17 Skewed Mucosal Innate‐like T Cell Signature

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