title: MAIT cells are licensed through granzyme exchange to kill bacterially sensitized targets.
abstract: Mucosal-associated invariant T (MAIT) cells are an innate-like T-cell population restricted by the non-polymorphic, major histocompatibility complex class I-related protein 1, MR1. MAIT cells are activated by a broad range of bacteria through detection of riboflavin metabolites bound by MR1, but their direct cytolytic capacity upon recognition of cognate target cells remains unclear. We show that resting human MAIT cells are uniquely characterized by a lack of granzyme (Gr) B and low perforin expression, key granule proteins required for efficient cytotoxic activity, but high levels of expression of GrA and GrK. Bacterial activation of MAIT cells rapidly induced GrB and perforin, licensing these cells to kill their cognate target cells. Using a novel flow cytometry-based killing assay, we show that licensed MAIT cells, but not ex vivo MAIT cells from the same donors, can efficiently kill Escherichia coli-exposed B-cell lines in an MR1- and degranulation-dependent manner. Finally, we show that MAIT cells are highly proliferative in response to antigenic and cytokine stimulation, maintaining high expression of GrB, perforin, and GrA, but reduced expression of GrK following antigenic proliferation. The tightly regulated cytolytic capacity of MAIT cells may have an important role in the control of intracellular bacterial infections, such as Mycobacterium tuberculosis.
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: A
authors.initials: A
authors.lastname: Kurioka
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: J E
authors.initials: JE
authors.lastname: Ussher
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: C
authors.initials: C
authors.lastname: Cosgrove
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: C
authors.initials: C
authors.lastname: Clough
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: J R
authors.initials: JR
authors.lastname: Fergusson
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: K
authors.initials: K
authors.lastname: Smith
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Kang
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: L J
authors.initials: LJ
authors.lastname: Walker
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, USA.
authors.forename: T H
authors.initials: TH
authors.lastname: Hansen
authors.affiliation: 1] Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK [2] National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
authors.forename: C B
authors.initials: CB
authors.lastname: Willberg
authors.affiliation: 1] Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK [2] National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
authors.forename: P
authors.initials: P
authors.lastname: Klenerman
mesh_terms: D001419:Bacteria / Q000276:immunology*; D015550:Cell Degranulation / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004926:Escherichia coli / Q000276:immunology; D015870:Gene Expression; D053804:Granzymes / Q000235:genetics* / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology; D015778:Minor Histocompatibility Antigens; D009092:Mucous Membrane / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D010581:Peyer's Patches / Q000166:cytology*; D010641:Phenotype; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: D015395:Histocompatibility Antigens Class I; C094840:MR1 protein, human; D015778:Minor Histocompatibility Antigens; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1; D053804:Granzymes