title: Functional Heterogeneity and Antimycobacterial Effects of Mouse Mucosal-Associated Invariant T Cells Specific for Riboflavin Metabolites.
abstract: Mucosal-associated invariant T (MAIT) cells have a semi-invariant TCR Vα-chain, and their optimal development is dependent upon commensal flora and expression of the nonpolymorphic MHC class I-like molecule MR1. MAIT cells are activated in an MR1-restricted manner by diverse strains of bacteria and yeast, suggesting a widely shared Ag. Recently, human and mouse MR1 were found to bind bacterial riboflavin metabolites (ribityllumazine [RL] Ags) capable of activating MAIT cells. In this study, we used MR1/RL tetramers to study MR1 dependency, subset heterogeneity, and protective effector functions important for tuberculosis immunity. Although tetramer(+) cells were detected in both MR1(+/+) and MR1(-/-) TCR Vα19i-transgenic (Tg) mice, MR1 expression resulted in significantly increased tetramer(+) cells coexpressing TCR Vβ6/8, NK1.1, CD44, and CD69 that displayed more robust in vitro responses to IL-12 plus IL-18 and RL Ag, indicating that MR1 is necessary for the optimal development of the classic murine MAIT cell memory/effector subset. In addition, tetramer(+) MAIT cells expressing CD4, CD8, or neither developing in MR1(+/+) Vα19i-Tg mice had disparate cytokine profiles in response to RL Ag. Therefore, murine MAIT cells are considerably more heterogeneous than previously thought. Most notably, after mycobacterial pulmonary infection, heterogeneous subsets of tetramer(+) Vα19i-Tg MAIT cells expressing CXCR3 and α4β1 were recruited into the lungs and afforded early protection. In addition, Vα19iCα(-/-)MR(+/+) mice were significantly better protected than were Vα19iCα(-/-)MR1(-/-), wild-type, and MR1(-/-) non-Tg mice. Overall, we demonstrate considerable functional diversity of MAIT cell responses, as well as that MR1-restricted MAIT cells are important for tuberculosis protective immunity.
authors.affiliation: Division of Infectious Diseases, Allergy, and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO 63104; Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110; hoftdf@slu.edu hansen@pathology.wustl.edu isaac.sakala@gmail.com.
authors.forename: Isaac G
authors.initials: IG
authors.lastname: Sakala
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Lars
authors.initials: L
authors.lastname: Kjer-Nielsen
authors.affiliation: Division of Infectious Diseases, Allergy, and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO 63104;
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Eickhoff
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110;
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Infectious Diseases, Allergy, and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO 63104;
authors.forename: Azra
authors.initials: A
authors.lastname: Blazevic
authors.affiliation: Division of Chemistry and Structural Biology, Institute of Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Queensland, Brisbane, Queensland 4072, Australia;
authors.forename: Ligong
authors.initials: L
authors.lastname: Liu
authors.affiliation: Division of Chemistry and Structural Biology, Institute of Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Queensland, Brisbane, Queensland 4072, Australia;
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Melbourne, Victoria 3800 Australia; Institute of Infection and Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom; Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia; and.
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110;
authors.forename: Daved H
authors.initials: DH
authors.lastname: Fremont
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110; hoftdf@slu.edu hansen@pathology.wustl.edu isaac.sakala@gmail.com.
authors.forename: Ted H
authors.initials: TH
authors.lastname: Hansen
authors.affiliation: Division of Infectious Diseases, Allergy, and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO 63104; Department of Microbiology and Immunology, Edward A. Doisy Research Center, Saint Louis University School of Medicine, Saint Louis, MO 63104 hoftdf@slu.edu hansen@pathology.wustl.edu isaac.sakala@gmail.com.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hoft
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental; D018740:Genetic Heterogeneity; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology; D018928:Immunity, Mucosal; D007156:Immunologic Memory; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D009163:Mycobacterium bovis / Q000276:immunology; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000235:genetics / Q000276:immunology; D055503:Protein Multimerization; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology; D012256:Riboflavin / Q000031:analogs & derivatives / Q000276:immunology* / Q000494:pharmacology; D015398:Signal Transduction; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology / Q000662:veterinary*; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000950:Antigens, Ly; D015395:Histocompatibility Antigens Class I; D018960:Hyaluronan Receptors; D039041:Integrin alpha4beta1; D018664:Interleukin-12; D020382:Interleukin-18; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; D055651:NK Cell Lectin-Like Receptor Subfamily B; D016693:Receptors, Antigen, T-Cell, alpha-beta; D054367:Receptors, CXCR3; D012256:Riboflavin; D000099192:CD69 Antigens; C476399:Cd44 protein, mouse; C515188:Cxcr3 protein, mouse; C527211:Klrb1c protein, mouse; C490628:Mr1 protein, mouse