title: Autophagy attenuates the adaptive immune response by destabilizing the immunologic synapse.
abstract: OBJECTIVE
  Variants in the genes ATG16L1 and IRGM affect autophagy and are associated with the development of Crohn's disease. It is not clear how autophagy is linked to loss of immune tolerance in the intestine. We investigated the involvement of the immunologic synapse-the site of contact between dendritic cells (DCs) and T cells, which contains molecules involved in antigen recognition and regulates immune response.
  
  
  METHODS
  DC autophagy was reduced using small interfering RNAs or pharmacologic inhibitors. DC phenotype and function were analyzed by confocal microscopy, time-lapse microscopy, and flow cytometry. We also examined DCs isolated from patients with Crohn's disease who carried the ATG16L1 risk allele.
  
  
  RESULTS
  Immunologic synapse formation induced formation of autophagosomes in DCs; the autophagosomes were oriented toward the immunologic synapse and contained synaptic components. Knockdown of ATG16L1 and IRGM with small interfering RNAs in DCs resulted in hyperstable interactions between DCs and T cells, increased activation of T cells, and activation of a T-helper 17 cell response. LKB1 was recruited to the immunologic synapse, and induction of autophagy in DC required inhibition of mammalian target of rapamycine signaling by the LKB1-AMP activated protein kinase (AMPK) pathway. DCs from patients with Crohn's disease who had an ATG16L1 risk allele had a similar hyperstability of the immunologic synapse.
  
  
  CONCLUSIONS
  Autophagy is induced upon formation of the immunologic synapse and negatively regulates T-cell activation. This mechanism might increase adaptive immunity in patients with Crohn's disease who carry ATG16L1 risk alleles.
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Manon E
authors.initials: ME
authors.lastname: Wildenberg
authors.forename: Anne Christine W
authors.initials: AC
authors.lastname: Vos
authors.forename: Simone C S
authors.initials: SC
authors.lastname: Wolfkamp
authors.forename: Marjolijn
authors.initials: M
authors.lastname: Duijvestein
authors.forename: Auke P
authors.initials: AP
authors.lastname: Verhaar
authors.forename: Anje A
authors.initials: AA
authors.lastname: Te Velde
authors.forename: Gijs R
authors.initials: GR
authors.lastname: van den Brink
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Hommes
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000276:immunology*; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D019204:GTP-Binding Proteins / Q000235:genetics / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D054992:Immunological Synapses / Q000276:immunology*; D051379:Mice; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology
chemical_list: C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D058570:TOR Serine-Threonine Kinases; D019204:GTP-Binding Proteins; C513539:IRGM protein, human