title: Mucosal-associated invariant T-cell activation and accumulation after in vivo infection depends on microbial riboflavin synthesis and co-stimulatory signals.
abstract: Despite recent breakthroughs in identifying mucosal-associated invariant T (MAIT) cell antigens (Ags), the precise requirements for in vivo MAIT cell responses to infection remain unclear. Using major histocompatibility complex-related protein 1 (MR1) tetramers, the MAIT cell response was investigated in a model of bacterial lung infection employing riboflavin gene-competent and -deficient bacteria. MAIT cells were rapidly enriched in the lungs of C57BL/6 mice infected with Salmonella Typhimurium, comprising up to 50% of αβ-T cells after 1 week. MAIT cell accumulation was MR1-dependent, required Ag derived from the microbial riboflavin synthesis pathway, and did not occur in response to synthetic Ag, unless accompanied by a Toll-like receptor agonist or by co-infection with riboflavin pathway-deficient S. Typhimurium. The MAIT cell response was associated with their long-term accumulation in the lungs, draining lymph nodes and spleen. Lung MAIT cells from infected mice displayed an activated/memory phenotype, and most expressed the transcription factor retinoic acid-related orphan receptor γt. T-bet expression increased following infection. The majority produced interleukin-17 while smaller subsets produced interferon-γ or tumor necrosis factor, detected directly ex vivo. Thus the activation and expansion of MAIT cells coupled with their pro-inflammatory cytokine production occurred in response to Ags derived from microbial riboflavin synthesis and was augmented by co-stimulatory signals.
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.|Animal Biotechnology, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Australia.
authors.forename: C
authors.initials: C
authors.lastname: D'Souza
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Kostenko
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
authors.forename: S B G
authors.initials: SB
authors.lastname: Eckle
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
authors.forename: B S
authors.initials: BS
authors.lastname: Meehan
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
authors.forename: D C
authors.initials: DC
authors.lastname: Jackson
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
authors.forename: R A
authors.initials: RA
authors.lastname: Strugnell
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Cao
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Wang
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.|Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, Australia.
authors.forename: D P
authors.initials: DP
authors.lastname: Fairlie
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.|Australian Research Council Centre of Excellence for Advanced Molecular Imaging, University of Melbourne, Parkville, Australia.
authors.forename: D I
authors.initials: DI
authors.lastname: Godfrey
authors.affiliation: Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia.|Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Australia.|Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, UK.
authors.forename: J
authors.initials: J
authors.lastname: Rossjohn
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
authors.forename: J
authors.initials: J
authors.lastname: McCluskey
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
authors.forename: A J
authors.initials: AJ
authors.lastname: Corbett
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D002478:Cells, Cultured; D061025:Costimulatory and Inhibitory T-Cell Receptors / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens / Q000378:metabolism*; D009092:Mucous Membrane / Q000276:immunology*; D055611:Natural Killer T-Cells / Q000276:immunology*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D012256:Riboflavin / Q000096:biosynthesis / Q000276:immunology; D012480:Salmonella Infections / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology*; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000098815:T-bet Transcription Factor
chemical_list: D000942:Antigens, Bacterial; D061025:Costimulatory and Inhibitory T-Cell Receptors; D015395:Histocompatibility Antigens Class I; D020381:Interleukin-17; D015778:Minor Histocompatibility Antigens; C490628:Mr1 protein, mouse; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D016693:Receptors, Antigen, T-Cell, alpha-beta; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D012256:Riboflavin