Format

Send to

Choose Destination
Cell. 2017 Oct 19;171(3):655-667.e17. doi: 10.1016/j.cell.2017.09.022.

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

Author information

1
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.
2
Department of Clinical Research (DKF), University of Bern, Inselspital, 3012 Bern, Switzerland.
3
Autoimmunity Research Group, Institut D'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain; Endocrinology & Nutrition Department, Hospital Clínic, 08036 Barcelona, Spain.
4
Department of Gastroenterology, Hospital Clinic and Institut D'Investigacions Biomediques August Pi i Sunyer, 08036 Barcelona, Spain.
5
Department of Microbiology, Immunology, and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary AB T2N 4N1, Canada.
6
Department of Immunology and Pathology, Monash University, Alfred Hospital Medical Research & Education Precinct, Melbourne VIC 3800, Australia.
7
Autoimmunity Research Group, Institut D'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain.
8
Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary AB T2N 4N1, Canada.
9
Department of Clinical Research (DKF), University of Bern, Inselspital, 3012 Bern, Switzerland. Electronic address: kathy.mccoy@ucalgary.ca.
10
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.

Abstract

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.

KEYWORDS:

Bacteroides Integrase; Cytotoxic T cells; Germ-free mice; Inflammatory bowel disease; Islet-specific glucose 6-phosphatase catalytic subunit-related protein (IGRP); Molecular mimicry

PMID:
29053971
DOI:
10.1016/j.cell.2017.09.022
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center