A Critical Role for Mucosal-Associated Invariant T Cells as Regulators and Therapeutic Targets in Systemic Lupus Erythematosus

Murayama, Goh; Chiba, Asako; Suzuki, Hitoshi; Nomura, Akihiro; Mizuno, Tomohiro; Kuga, Takashi; Nakamura, Shinji; Amano, Hirofumi; Hirose, Sachiko; Yamaji, Katsuhiko; Suzuki, Yusuke; Tamura, Naoto; Miyake, Sachiko

doi:10.3389/fimmu.2019.02681

Cited by 44 publications

(68 citation statements)

References 46 publications

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“…Models of infection with bacterial pathogens in mice ( 32 – 34 , 54 ) and non-human primates ( 147 ) have revealed much about MAIT cell biology and their role in protective immunity. The development of MR1-5-OP-RU-tetramer reagents ( 7 , 11 ) has enabled the specific assessment of MAIT cells in naïve SPF-housed mice ( 67 , 130 , 148 ), in disease-relevant models including infection, autoimmune disease ( 35 , 149 , 150 ), transplantation ( 151 ) and cancer ( 152 ), and MAIT cell development ( 55 , 71 , 153 ). MR1-tetramers also allow the assessment of the ability of defined compounds to act as antigens, with 5-OP-RU ( 67 , 93 ), premixed 5-A-RU and methylglyoxal ( 25 , 123 ) and a pro-drug designed to release 5-A-RU ( 123 ) all shown to boost MAIT cell numbers in mice, in the presence of TLR agonists or other co-stimuli.…”

Section: Tools For the Assessment Of Mr1 Ligand Production And Recognmentioning

confidence: 99%

Antigen Recognition by MR1-Reactive T Cells; MAIT Cells, Metabolites, and Remaining Mysteries

et al. 2020

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Mucosal-associated Invariant T (MAIT) cells recognize vitamin B-based antigens presented by the non-polymorphic MHC class I related-1 molecule (MR1). Both MAIT T cell receptors (TCR) and MR1 are highly conserved among mammals, suggesting an important, and conserved, immune function. For many years, the antigens they recognize were unknown. The discovery that MR1 presents vitamin B-based small molecule ligands resulted in a rapid expansion of research in this area, which has yielded information on the role of MAIT cells in immune protection, autoimmune disease and recently in homeostasis and cancer. More recently, we have begun to appreciate the diverse nature of the small molecule ligands that can bind MR1, with several less potent antigens and small molecule drugs that can bind MR1 being identified. Complementary structural information has revealed the complex nature of interactions defining antigen recognition. Additionally, we now view MAIT cells (defined here as MR1-riboflavin-Ag reactive, TRAV1-2 + cells) as one subset of a broader family of MR1-reactive T cells (MR1T cells). Despite these advances, we still lack a complete understanding of how MR1 ligands are generated, presented and recognized in vivo . The biological relevance of these MR1 ligands and the function of MR1T cells in infection and disease warrants further investigation with new tools and approaches.

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Section: Tools For the Assessment Of Mr1 Ligand Production And Recognmentioning

confidence: 99%

Antigen Recognition by MR1-Reactive T Cells; MAIT Cells, Metabolites, and Remaining Mysteries

et al. 2020

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“…In patients with vitiligo, IFN‐γ and IL‐17 will, respectively, elicit enhanced depigmentation, while melanoma patients will experience enhanced antitumor immunity. In fact, a role for MAIT cells in autoimmune disease, accompanied by lower numbers of circulating MAIT cells (normally around 10% (Pellicci et al., 2020)), has now been proposed in several skin conditions (Murayama et al., 2019; Toubal et al., 2019). MAIT cells can also be activated by tumors cells (Zumwalde et al., 2018), and their role in responding to microbial metabolites can help us understand how microorganisms can support T cell–mediated adaptive immune responses, converting the outcome into an autoimmune or antitumor response in some hosts.…”

Section: First Responders From Dendritic Cells To Innate Lymphocytesmentioning

confidence: 99%

Myron Gordon Award paper: Microbes, T‐cell diversity and pigmentation

Poole

2021

Pigment Cell Melanoma Res

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Melanocytes are static, minimally proliferative cells. This leaves them vulnerable in vitiligo. Yet upon malignant transformation, they form vicious tumors. This profound switch in physiology is accompanied by genetic change and is driven by environmental factors. If UV exposure in younger years supports malignant transformation and melanoma formation, it can likewise impart mutations on melanocytes that reduce their viability, to initiate vitiligo. A wide variety of microbes can influence these diametrically opposed outcomes before either disease takes hold. These microbes are vehicles of change that we are only beginning to study. Once a genetic modification occurs, there is a wide variety of immune cells ready to respond. Though it does not act alone, the T cell is among the most decisive responders in this process. The same biochemical process that offered the skin protection by producing melanin can become an Achilles heel for the cell when the T cells target melanosomal enzymes or, on occasion, neoantigens. T cells are precise, determined, and consequential when they strike. Here, we probe the relationship between the microbiome and its metabolites, epithelial integrity, and the activation of T cells that target benign and malignant melanocytes in vitiligo and melanoma.

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“…Inhibitory ligands have the potential to be used to downregulate MAIT cell activation. Indeed, a synthetic derivative of the vitamin B9 metabolite 6-FP (i-6FP) has been used to inhibit MAIT cell activation and improve the course of the autoimmune disease lupus in FcγRIIb −/− mice, a spontaneous model of systemic lupus erythematosus in which MAIT cells have been shown to enhance autoantibody production and tissue inflammation ( 45 ).…”

Section: Tight Regulation Of Mait Cell Activationmentioning

confidence: 99%

“…The observation that in Vibrio cholera infection ( 99 ) and Shigella dysenteriae vaccination ( 24 ) the circulating frequency of MAIT cells correlates with the pathogen-specific antibody response suggests some form of helper activity from MAIT cells. In a murine model of lupus, MAIT cell activity correlates with autoantibodies, germinal center reaction, and severity of disease ( 45 ). In this paper, the authors also reported that, in vitro , MAIT cells enhanced IgG production by LPS-stimulated B cells through CD40-CD40L cognate interactions ( 45 ).…”

Section: Mait Cells: the New Inkt/γδ T Cells?mentioning

confidence: 99%

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The Immune Modulating Properties of Mucosal-Associated Invariant T Cells

2020

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Mucosal-associated invariant T (MAIT) cells are unconventional T lymphocytes that express a semi-invariant T cell receptor (TCR) recognizing microbial vitamin B metabolites presented by the highly conserved major histocompatibility complex (MHC) class I like molecule, MR1. The vitamin B metabolites are produced by several commensal and pathogenic bacteria and yeast, but not viruses. Nevertheless, viral infections can trigger MAIT cell activation in a TCR-independent manner, through the release of pro-inflammatory cytokines by antigen-presenting cells (APCs). MAIT cells belong to the innate like T family of cells with a memory phenotype, which allows them to rapidly release Interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and in some circumstances Interleukin (IL)-17 and IL-10, exerting an immunomodulatory role on the ensuing immune response, akin to iNKT cells and γδ T cells. Recent studies implicate MAIT cells in a variety of inflammatory, autoimmune diseases, and in cancer. In addition, through the analysis of the transcriptome of MAIT cells activated in different experimental conditions, an important function in tissue repair and control of immune homeostasis has emerged, shared with other innate-like T cells. In this review, we discuss these recent findings, focussing on the understanding of the molecular mechanisms underpinning MAIT cell activation and effector function in health and disease, which ultimately will aid in clinically harnessing this unique, not donor-restricted cell subtype.

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A Critical Role for Mucosal-Associated Invariant T Cells as Regulators and Therapeutic Targets in Systemic Lupus Erythematosus

Cited by 44 publications

References 46 publications

Antigen Recognition by MR1-Reactive T Cells; MAIT Cells, Metabolites, and Remaining Mysteries

Antigen Recognition by MR1-Reactive T Cells; MAIT Cells, Metabolites, and Remaining Mysteries

Myron Gordon Award paper: Microbes, T‐cell diversity and pigmentation

The Immune Modulating Properties of Mucosal-Associated Invariant T Cells

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