Journal
NATURE MEDICINE
Volume 16, Issue 1, Pages 90-U128Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2069
Keywords
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Funding
- UK Medical Research Council
- UK Higher Education Funding Council
- Oxford National Institute for Health Research Biomedical Research Centre
- National Institute of Health Research Specialist Biomedical Research Centre in Microbial Disease [01CD1]
- Action Medical Research
- Digestive Disorders Foundation and National Association for Crohn's and Colitis and The Barbour Trust in Memory of Simon Ash
- Fondation Philippe Weiner Maurice Anspach
- Wellcome Trust
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Nucleotide-binding oligomerization domain-containing-2 (NOD2) acts as a bacterial sensor in dendritic cells (DCs), but it is not clear how bacterial recognition links with antigen presentation after NOD2 stimulation. NOD2 variants are associated with Crohn's disease, where breakdown in self-recognition of commensal bacteria leads to gastrointestinal inflammation. Here we show NOD2 triggering by muramyldipeptide induces autophagy in DCs. This effect requires receptor-interacting serine-threonine kinase-2 (RIPK-2), autophagy-related protein-5 (ATG5), ATG7 and ATG16L1 but not NLR family, pyrin domain containing-3 (NALP3). We show that NOD2-mediated autophagy is required for both bacterial handling and generation of major histocompatibility complex (MHC) class II antigen-specific CD4(+) T cell responses in DCs. DCs from individuals with Crohn's disease expressing Crohn's disease-associated NOD2 or ATG16L1 risk variants are defective in autophagy induction, bacterial trafficking and antigen presentation. Our findings link two Crohn's disease-associated susceptibility genes in a single functional pathway and reveal defects in this pathway in Crohn's disease DCs that could lead to bacterial persistence via impaired lysosomal destruction and immune mediated clearance.
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