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A Gut Microbial Mimic that Hijacks Diabetogenic Autoreactivity to Suppress Colitis.

  • Hebbandi Nanjundappa R Julia McFarlane Diabetes Research Centre (JMDRC), University of Calgary, Calgary AB T2N 4N1, Canada; Department of Microbiology, Immunology, and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary AB T2N 4N1, Canada.
  • Ronchi F Department of Clinical Research (DKF), University of Bern, Inselspital, 3012 Bern, Switzerland.
  • Wang J Julia McFarlane Diabetes Research Centre (JMDRC), University of Calgary, Calgary AB T2N 4N1, Canada; Department of Microbiology, Immunology, and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary AB T2N 4N1, Canada.
  • Clemente-Casares X Julia McFarlane Diabetes Research Centre (JMDRC), University of Calgary, Calgary AB T2N 4N1, Canada; Department of Microbiology, Immunology, and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary AB T2N 4N1, Canada.
  • Yamanouchi J Julia McFarlane Diabetes Research Centre (JMDRC), University of Calgary, Calgary AB T2N 4N1, Canada; Department of Microbiology, Immunology, and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary AB T2N 4N1, Canada.
  • Sokke Umeshappa C Julia McFarlane Diabetes Research Centre (JMDRC), University of Calgary, Calgary AB T2N 4N1, Canada; Department of Microbiology, Immunology, and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary AB T2N 4N1, Canada.
  • Yang Y Julia McFarlane Diabetes Research Centre (JMDRC), University of Calgary, Calgary AB T2N 4N1, Canada; Department of Microbiology, Immunology, and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary AB T2N 4N1, Canada.
  • Blanco J Autoimmunity Research Group, Institut D'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain; Endocrinology & Nutrition Department, Hospital Clínic, 08036 Barcelona, Spain.
  • Bassolas-Molina H Department of Gastroenterology, Hospital Clinic and Institut D'Investigacions Biomediques August Pi i Sunyer, 08036 Barcelona, Spain.
  • Salas A Department of Gastroenterology, Hospital Clinic and Institut D'Investigacions Biomediques August Pi i Sunyer, 08036 Barcelona, Spain.
  • Khan H Department of Microbiology, Immunology, and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary AB T2N 4N1, Canada.
  • Slattery RM Department of Immunology and Pathology, Monash University, Alfred Hospital Medical Research & Education Precinct, Melbourne VIC 3800, Australia.
  • Wyss M Department of Clinical Research (DKF), University of Bern, Inselspital, 3012 Bern, Switzerland.
  • Mooser C Department of Clinical Research (DKF), University of Bern, Inselspital, 3012 Bern, Switzerland.
  • Macpherson AJ Department of Clinical Research (DKF), University of Bern, Inselspital, 3012 Bern, Switzerland.
  • Sycuro LK Department of Microbiology, Immunology, and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary AB T2N 4N1, Canada.
  • Serra P Autoimmunity Research Group, Institut D'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain.
  • McKay DM Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary AB T2N 4N1, Canada.
  • McCoy KD Department of Clinical Research (DKF), University of Bern, Inselspital, 3012 Bern, Switzerland. Electronic address: kathy.mccoy@ucalgary.ca.
  • Santamaria P Julia McFarlane Diabetes Research Centre (JMDRC), University of Calgary, Calgary AB T2N 4N1, Canada; Autoimmunity Research Group, Institut D'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain; Department of Microbiology, Immunology, and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary AB T2N 4N1, Canada. Electronic address: psantama@ucalgary.ca.
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  • 2017-10-21
Published in:
  • Cell. - 2017
Bacteroides Integrase
Cytotoxic T cells
Germ-free mice
Inflammatory bowel disease
Islet-specific glucose 6-phosphatase catalytic subunit-related protein (IGRP)
Molecular mimicry
Adult
Animals
Autoantigens
Bacteroides
Colitis
Female
Gastrointestinal Microbiome
Glucose-6-Phosphatase
Humans
Lymphoid Tissue
Male
Mice
Mice, Inbred BALB C
Mice, Inbred NOD
Middle Aged
Molecular Mimicry
T-Lymphocytes
English The gut microbiota contributes to the development of normal immunity but, when dysregulated, can promote autoimmunity through various non-antigen-specific effects on pathogenic and regulatory lymphocytes. Here, we show that an integrase expressed by several species of the gut microbial genus Bacteroides encodes a low-avidity mimotope of the pancreatic β cell autoantigen islet-specific glucose-6-phosphatase-catalytic-subunit-related protein (IGRP206-214). Studies in germ-free mice monocolonized with integrase-competent, integrase-deficient, and integrase-transgenic Bacteroides demonstrate that the microbial epitope promotes the recruitment of diabetogenic CD8+ T cells to the gut. There, these effectors suppress colitis by targeting microbial antigen-loaded, antigen-presenting cells in an integrin β7-, perforin-, and major histocompatibility complex class I-dependent manner. Like their murine counterparts, human peripheral blood T cells also recognize Bacteroides integrase. These data suggest that gut microbial antigen-specific cytotoxic T cells may have therapeutic value in inflammatory bowel disease and unearth molecular mimicry as a novel mechanism by which the gut microbiota can regulate normal immune homeostasis. PAPERCLIP.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://sonar.ch/global/documents/278623
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