Cytotoxic and regulatory roles of mucosal-associated invariant T cells in type 1 diabetes

Rouxel, Ophélie; Silva, Jennifer Da; Beaudoin, Lucie; Nel, Isabelle; Tard, Céline; Cagninacci, Lucie; Kiaf, Badr; Oshima, Masaya; Diedisheim, Marc; Salou, Marion; Corbett, Alexandra J.; Rossjohn, Jamie; McCluskey, James; Scharfmann, Raphaël; Battaglia, Manuela; Polak, Michel; Lantz, Olivier; Beltrand, Jacques; Lehuen, Agnès

doi:10.1038/ni.3854

Cited by 206 publications

(224 citation statements)

References 63 publications

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“…The in vivo significance of MAIT cell‐mediated cytotoxicity may not be limited to infectious diseases and cancer. In fact, this function has been recently linked to autoimmune diabetes . While autoimmunity is beyond the scope of this review, it is worth mentioning that the cytolytic profile and function of human MAIT cells were implicated in the pathogenesis and severity of type 1 diabetes.…”

Section: Outstanding Questions and Concluding Remarksmentioning

confidence: 99%

MAIT cell-mediated cytotoxicity: Roles in host defense and therapeutic potentials in infectious diseases and cancer

Rudak

Choi

Haeryfar

2018

Journal of Leukocyte Biology

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Mucosa-associated invariant T (MAIT) cells are unconventional, innate-like T lymphocytes that sense the presence of MHC-related protein 1 (MR1)-restricted ligands and select inflammatory cues. Consequently, they release potent immunomodulatory mediators, including IFN-γ, TNF-α, and/or IL-17. MAIT cells can also be viewed as killer cells. They display several NK cell-associated receptors, carry granules containing cytotoxic effector molecules, and swiftly upregulate perforin and granzymes upon activation. Accordingly, MAIT cells are capable of lysing MR1-expressing cells infected with a variety of pathogenic bacteria in in vitro settings and may also mount cytotoxic responses during microbial infections in vivo. Of note, MAIT cell hyperactivation during certain infections may impede their ability to elicit inflammatory and/or cytotoxic responses to secondary stimuli. In addition, MAIT cells isolated from within and from the margin of tumor masses exhibit diminished functions. We propose that MAIT cell-mediated cytotoxicity can be induced, bolstered, or restored to assist in clearing infections and potentially in reducing tumor loads. In this review, we discuss our current understanding of MAIT cells' lytic functions and highlight the pressing questions that need to be addressed in future investigations. We also offer a picture, however hypothetical at this point, of how harnessing the full cytotoxic potentials of MAIT cells may be a valuable approach in the immunotherapy of infectious and malignant diseases.

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Section: Outstanding Questions and Concluding Remarksmentioning

confidence: 99%

MAIT cell-mediated cytotoxicity: Roles in host defense and therapeutic potentials in infectious diseases and cancer

Rudak

Choi

Haeryfar

2018

Journal of Leukocyte Biology

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“…The discovery of 5‐OP‐RU and 5‐OE‐RU as very potent Ags and the development of MR1‐tetramers, now available from the National Institutes of Health, USA, have opened up the field to start elucidating the roles of MAIT cells in anti‐microbial immunity, in sensing of metabolic changes such as in cancer, stress and cell damage, as well as in immunopathology . The tetramers have also allowed further characterization of the phenotypic identity of MAIT cells and their development, with individual‐ and age‐specific differences now being investigated .…”

Section: Discovery Of Mr1 Bound Antigens That Activate Mait Cellsmentioning

confidence: 99%

An overview on the identification of MAIT cell antigens

et al. 2018

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Mucosal associated invariant T (MAIT) cells are restricted by the monomorphic MHC class I-like molecule, MHC-related protein-1 (MR1). Until 2012, the origin of the MAIT cell antigens (Ags) was unknown, although it was established that MAIT cells could be activated by a broad range of bacteria and yeasts, possibly suggesting a conserved Ag. Using a combination of protein chemistry, mass spectrometry, cellular biology, structural biology and small molecule chemistry, we discovered MR1 ligands derived from folic acid (vitamin B9) and from an intermediate in the microbial biosynthesis of riboflavin (vitamin B2). While the folate derivative 6-formylpterin generally inhibited MAIT cell activation, two riboflavin pathway derivatives, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil and 5-(2-oxoethylideneamino)-6-D-ribitylaminouracil, were potent MAIT cell agonists. Other intermediates and derivatives of riboflavin synthesis displayed weak or no MAIT cell activation. Collectively, these studies revealed that in addition to peptide and lipid-based Ags, small molecule natural product metabolites are also ligands that can activate T cells expressing αβ T-cell receptors, and here we recount this discovery.

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“…MAIT cells have the capacity to directly respond to bacterial and fungal pathogens and are located to selectively protect mucosal barriers . In addition, MAIT cells have been implicated in diseases such as asthma and type 1 diabetes . Recently, it has been suggested that MAIT cells confer partial protection from Graft‐ versus ‐Host‐Disease after bone marrow transplantation …”

Section: Introductionmentioning

confidence: 99%

MicroRNA miR‐181a/b‐1 controls MAIT cell development

et al. 2018

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Mucosal‐associated invariant T (MAIT) cells constitute a major fraction of innate‐like T cells in humans with critical roles in defense against microbial pathogens and in maintaining mucosal integrity. However, the molecular mechanisms underlying MAIT cell development remain largely elusive. Here we investigated the role of miR‐181a/b‐1, a pair of microRNAs that serve as rheostat of TCR signal strength, in this process. Loss of miR‐181a/b‐1 in mice resulted in a profound arrest in early MAIT cell development. As a consequence, in the absence of miR‐181a/b‐1, thymic MAIT cells failed to acquire functional maturity based on expression of transcription factors PLZF, T‐bet and RORγt. Temporal analysis of development using a molecular timer in combination with loss of miR‐181a/b‐1 revealed that MAIT cells complete functional maturation in the periphery and indicates that functionally mature MAIT cells in the thymus are long‐term resident cells. Thus, our study provides insight into the dynamics of MAIT cell development in vivo. Of note, deletion of miR‐181a/b‐1 alone completely mirrored loss of all miRNAs.

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Cytotoxic and regulatory roles of mucosal-associated invariant T cells in type 1 diabetes

Cited by 206 publications

References 63 publications

MAIT cell-mediated cytotoxicity: Roles in host defense and therapeutic potentials in infectious diseases and cancer

MAIT cell-mediated cytotoxicity: Roles in host defense and therapeutic potentials in infectious diseases and cancer

An overview on the identification of MAIT cell antigens

MicroRNA miR‐181a/b‐1 controls MAIT cell development

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