Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis

Nat Immunol. 2016 Mar;17(3):277-85. doi: 10.1038/ni.3365. Epub 2016 Jan 25.

Abstract

Regulatory T (Treg) cells respond to immune and inflammatory signals to mediate immunosuppression, but how the functional integrity of Treg cells is maintained under activating environments is unclear. Here we show that autophagy is active in Treg cells and supports their lineage stability and survival fitness. Treg cell-specific deletion of Atg7 or Atg5, two essential genes in autophagy, leads to loss of Treg cells, greater tumor resistance and development of inflammatory disorders. Atg7-deficient Treg cells show increased apoptosis and readily lose expression of the transcription factor Foxp3, especially after activation. Mechanistically, autophagy deficiency upregulates metabolic regulators mTORC1 and c-Myc and glycolysis, which contribute to defective Treg function. Therefore, autophagy couples environmental signals and metabolic homeostasis to protect lineage and survival integrity of Treg cells in activating contexts.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / immunology
  • Adoptive Transfer
  • Animals
  • Apoptosis / genetics*
  • Apoptosis / immunology
  • Autophagy / genetics*
  • Autophagy / immunology
  • Autophagy-Related Protein 5
  • Autophagy-Related Protein 7
  • Cell Line, Tumor
  • Colonic Neoplasms / immunology
  • DNA Methylation
  • Flow Cytometry
  • Forkhead Transcription Factors / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Glycolysis
  • Homeostasis
  • Immunoblotting
  • Lymphocyte Activation / immunology
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / genetics*
  • Multiprotein Complexes / metabolism*
  • Neoplasm Transplantation
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Real-Time Polymerase Chain Reaction
  • T-Lymphocytes, Regulatory / immunology*
  • TOR Serine-Threonine Kinases / metabolism*
  • Up-Regulation

Substances

  • Atg5 protein, mouse
  • Atg7 protein, mouse
  • Autophagy-Related Protein 5
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Microtubule-Associated Proteins
  • Multiprotein Complexes
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Autophagy-Related Protein 7