title: MR1-restricted MAIT cells display ligand discrimination and pathogen selectivity through distinct T cell receptor usage.
abstract: Mucosal-associated invariant T (MAIT) cells express a semi-invariant T cell receptor (TCR) that detects microbial metabolites presented by the nonpolymorphic major histocompatibility complex (MHC)-like molecule MR1. The highly conserved nature of MR1 in conjunction with biased MAIT TCRα chain usage is widely thought to indicate limited ligand presentation and discrimination within a pattern-like recognition system. Here, we evaluated the TCR repertoire of MAIT cells responsive to three classes of microbes. Substantial diversity and heterogeneity were apparent across the functional MAIT cell repertoire as a whole, especially for TCRβ chain sequences. Moreover, different pathogen-specific responses were characterized by distinct TCR usage, both between and within individuals, suggesting that MAIT cell adaptation was a direct consequence of exposure to various exogenous MR1-restricted epitopes. In line with this interpretation, MAIT cell clones with distinct TCRs responded differentially to a riboflavin metabolite. These results suggest that MAIT cells can discriminate between pathogen-derived ligands in a clonotype-dependent manner, providing a basis for adaptive memory via recruitment of specific repertoires shaped by microbial exposure.
authors: Division of Pulmonary and Critical Care Medicine, Department of Molecular Microbiology and Immunology, and Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239Division of Pulmonary and Critical Care Medicine, Department of Molecular Microbiology and Immunology, and Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239 Portland VA Medical Center, Portland, OR 97239 goldm@ohsu.edu lewinsod@ohsu.edu.
authors: Marielle C
authors: MC
authors: Gold
authors: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, Wales, UK.
authors: James E
authors: JE
authors: McLaren
authors: Division of Pulmonary and Critical Care Medicine, Department of Molecular Microbiology and Immunology, and Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239.
authors: Joseph A
authors: JA
authors: Reistetter
authors: Division of Pulmonary and Critical Care Medicine, Department of Molecular Microbiology and Immunology, and Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239.
authors: Sue
authors: S
authors: Smyk-Pearson
authors: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, Wales, UK.
authors: Kristin
authors: K
authors: Ladell
authors: Division of Pulmonary and Critical Care Medicine, Department of Molecular Microbiology and Immunology, and Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239.
authors: Gwendolyn M
authors: GM
authors: Swarbrick
authors: Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110.
authors: Yik Y L
authors: YY
authors: Yu
authors: Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110.
authors: Ted H
authors: TH
authors: Hansen
authors: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark.
authors: Ole
authors: O
authors: Lund
authors: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín, 1650 San Martín, Buenos Aires, Argentina.
authors: Morten
authors: M
authors: Nielsen
authors: Theoretical Biology and Bioinformatics Group, Utrecht University, 3584 CH Utrecht, Netherlands.
authors: Bram
authors: B
authors: Gerritsen
authors: Theoretical Biology and Bioinformatics Group, Utrecht University, 3584 CH Utrecht, Netherlands.
authors: Can
authors: C
authors: Kesmir
authors: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, Wales, UK QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors: John J
authors: JJ
authors: Miles
authors: Division of Pulmonary and Critical Care Medicine, Department of Molecular Microbiology and Immunology, and Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239Division of Pulmonary and Critical Care Medicine, Department of Molecular Microbiology and Immunology, and Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239.
authors: Deborah A
authors: DA
authors: Lewinsohn
authors: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, Wales, UK Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors: David A
authors: DA
authors: Price
authors: Division of Pulmonary and Critical Care Medicine, Department of Molecular Microbiology and Immunology, and Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239Division of Pulmonary and Critical Care Medicine, Department of Molecular Microbiology and Immunology, and Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239 Portland VA Medical Center, Portland, OR 97239 goldm@ohsu.edu lewinsod@ohsu.edu.
authors: David M
authors: DM
authors: Lewinsohn
mesh_terms: D000595:Amino Acid Sequence; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D001419:Bacteria / Q000187:drug effects / Q000276:immunology*; D002460:Cell Line; D002999:Clone Cells; D022801:Complementarity Determining Regions / Q000737:chemistry; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D009092:Mucous Membrane / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D014803:Vitamin B Complex / Q000494:pharmacology
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D022801:Complementarity Determining Regions; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D008024:Ligands; C094840:MR1 protein, human; D015778:Minor Histocompatibility Antigens; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; C045084:invariant chain; D014803:Vitamin B Complex