Format

Send to

Choose Destination
See comment in PubMed Commons below
Gastroenterology. 2012 Jun;142(7):1493-503.e6. doi: 10.1053/j.gastro.2012.02.034. Epub 2012 Feb 24.

Autophagy attenuates the adaptive immune response by destabilizing the immunologic synapse.

Author information

1
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.

Abstract

BACKGROUND & AIMS:

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.

PMID:
22370477
DOI:
10.1053/j.gastro.2012.02.034
[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science
    Loading ...
    Support Center