Human MAIT Cell Activation In Vitro

Hagel, Joachim; Garner, Lucy C.; Bilton, Matthew; Mehta, Hema; Leng, Tianqi; Hackstein, Carl-Philipp; Phalora, Prabhjeet; Amini, Ali; Akther, Hossain Delowar; Provine, Nicholas M.; Edmans, Matthew; Willberg, Christian; Klenerman, Paul

doi:10.1007/978-1-0716-0207-2_7

Cited by 14 publications

(13 citation statements)

References 31 publications

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“…This highlights the danger of inferring antigen identity when using whole-cell assays to test for MAIT cell activation. To limit the complexity relative to the cell systems, plate-bound MR1 has also been utilized in a similar activation assay ( 141 ). The direct elution of MR1-bound ligands from immunoprecipitated cell surface MR1 for identification by mass spectrometry is technically challenging, but has been shown using C1R cells overexpressing MR1 (C1R.MR1 cells) for Ac-6-FP, 3-F-SA and diclofenac metabolites ( 28 ).…”

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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“…5-OP-RU was added for 20 h to the co-culture of MAIT cells and monocytes. As in other bicellular studies, MAIT cells were stimulated by using a concentration of 50 ng/ml 5-OP-RU, which induces efficient pro-inflammatory responses while maintaining viability of MAIT cells ( Hagel et al, 2020 ). For intracellular staining, Brefeldin A was added for the last 4 h of stimulation.…”

Section: Methodsmentioning

confidence: 99%

Clostridioides difficile Toxin CDT Induces Cytotoxic Responses in Human Mucosal-Associated Invariant T (MAIT) Cells

et al. 2021

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Clostridioides difficile is the major cause of antibiotic-associated colitis (CDAC) with increasing prevalence in morbidity and mortality. Severity of CDAC has been attributed to hypervirulent C. difficile strains, which in addition to toxin A and B (TcdA, TcdB) produce the binary toxin C. difficile transferase (CDT). However, the link between these toxins and host immune responses as potential drivers of immunopathology are still incompletely understood. Here, we provide first experimental evidence that C. difficile toxins efficiently activate human mucosal-associated invariant T (MAIT) cells. Among the tested toxins, CDT and more specifically, the substrate binding and pore-forming subunit CDTb provoked significant MAIT cell activation resulting in selective MAIT cell degranulation of the lytic granule components perforin and granzyme B. CDT-induced MAIT cell responses required accessory immune cells, and we suggest monocytes as a potential CDT target cell population. Within the peripheral blood mononuclear cell fraction, we found increased IL-18 levels following CDT stimulation and MAIT cell response was indeed partly dependent on this cytokine. Surprisingly, CDT-induced MAIT cell activation was found to be partially MR1-dependent, although bacterial-derived metabolite antigens were absent. However, the role of antigen presentation in this process was not analyzed here and needs to be validated in future studies. Thus, MR1-dependent induction of MAIT cell cytotoxicity might be instrumental for hypervirulent C. difficile to overcome cellular barriers and may contribute to pathophysiology of CDAC.

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“…The invariant TCR is sensitive to riboflavin metabolites generated by yeast and bacterial species that can activate MAIT cells through this receptor (Toubal et al., 2019). MAIT cells are activated when riboflavin metabolites are presented to them as processed by dendritic cells (in the context of MR1) but can also be activated directly by the cytokine IL‐18 (Hagel et al., 2020), thereby amplifying the local inflammation. MAIT cell activation is regulated in part by co‐receptor NKG2D, and activation leads to dual secretion of IL‐17 and IFN‐γ (Zumwalde et al., 2018) to help sense and control microbial infections, and restore tissue homeostasis.…”

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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Human MAIT Cell Activation In Vitro

Cited by 14 publications

References 31 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

Clostridioides difficile Toxin CDT Induces Cytotoxic Responses in Human Mucosal-Associated Invariant T (MAIT) Cells

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

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