TLR signaling in human antigen-presenting cells regulates MR1-dependent activation of MAIT cells.
Mucosal-associated invariant T (MAIT) cells are an abundant innate-like T lymphocyte population that are enriched in liver and mucosal tissues. They are restricted by MR1, which presents antigens derived from a metabolic precursor of riboflavin synthesis, a pathway present in many microbial species, including commensals. Therefore, MR1-mediated MAIT cell activation must be tightly regulated to prevent inappropriate activation and immunopathology. Using an in vitro model of MR1-mediated activation of primary human MAIT cells, we investigated the mechanisms by which it is regulated. Uptake of intact bacteria by antigen presenting cells (APCs) into acidified endolysosomal compartments was required for efficient MR1-mediated MAIT cell activation, while stimulation with soluble ligand was inefficient. Consistent with this, little MR1 was seen at the surface of human monocytic (THP1) and B-cell lines. Activation with a TLR ligand increased the amount of MR1 at the surface of THP1 but not B-cell lines, suggesting differential regulation in different cell types. APC activation and NF-κB signaling were critical for MR1-mediated MAIT cell activation. In primary cells, however, prolonged TLR signaling led to downregulation of MR1-mediated MAIT cell activation. Overall, MR1-mediated MAIT cell activation is a tightly regulated process, dependent on integration of innate signals by APCs.
Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, Oxfordshire, United Kingdom.|Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
James E
JE
Ussher
Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, Oxfordshire, United Kingdom.
Bonnie
B
van Wilgenburg
Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
Rachel F
RF
Hannaway
Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, Oxfordshire, United Kingdom.
Kerstin
K
Ruustal
Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, Oxfordshire, United Kingdom.
Prabhjeet
P
Phalora
Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, Oxfordshire, United Kingdom.
Ayako
A
Kurioka
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
Ted H
TH
Hansen
Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, Oxfordshire, United Kingdom.|Oxford NIHR Biomedical Research Centre, The John Radcliffe Hospital, Oxford, United Kingdom.
Christian B
CB
Willberg
Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, Oxfordshire, United Kingdom.
Rodney E
RE
Phillips
Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, Oxfordshire, United Kingdom.|Oxford NIHR Biomedical Research Centre, The John Radcliffe Hospital, Oxford, United Kingdom.
Paul
P
Klenerman
D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism*; D000941:Antigens / Q000276:immunology; D001419:Bacteria / Q000276:immunology; D002462:Cell Membrane / Q000378:metabolism; D011992:Endosomes / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D015778:Minor Histocompatibility Antigens / Q000378:metabolism*; D000072336:Mucosal-Associated Invariant T Cells / Q000276:immunology* / Q000378:metabolism*; D009092:Mucous Membrane / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*
D000941:Antigens; D015395:Histocompatibility Antigens Class I; D020382:Interleukin-18; D008024:Ligands; D008070:Lipopolysaccharides; C094840:MR1 protein, human; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D051193:Toll-Like Receptors; D018664:Interleukin-12
Activation; Antigen presenting cell; Endotoxin tolerance; MAIT cells; MR1; NF-κB