科研之友
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摘要
BACKGROUND %26 AIMS: Variants in the genes ATG16L1 and IRGM affect autophagy and are associated with the development of Crohn%26apos;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%26apos;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%26apos;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%26apos;s disease who carry ATG16L1 risk alleles.
- 出版日期2012-6
