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PMID: 26808230 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature immunology ·Vol. 17 ·No. 3 ·2016-03-00 ·Pages 277-85

Wei J, Long L, Yang K, Guy C, Shrestha S, Chen Z, Wu C, Vogel P, Neale G, Green DR, Chi H

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.

MeSH Terms
Adenocarcinoma/immunology Adoptive Transfer Animals Apoptosis/genetics,immunology Autophagy/genetics,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
Chemicals
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 Mechanistic Target of Rapamycin Complex 1 TOR Serine-Threonine Kinases Autophagy-Related Protein 7
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Wei Jun
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Long Lingyun
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Yang Kai
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Guy Cliff
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Shrestha Sharad
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Chen Zuojia
Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Wu Chuan
Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Vogel Peter
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Neale Geoffrey
Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Green Douglas R
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Chi Hongbo
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
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Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.3365
Published
2016-03-00
Epub
2016-00-25
Pages
277-85
Language
English
Region
United States
NLM ID
100941354
PMCID
PMC4755832
Subset
IM
Grants
NINDS NIH HHS · R01 NS064599 · United States
NCI NIH HHS · P30 CA021765 · United States
NIAID NIH HHS · R01 AI101407 · United States
NCI NIH HHS · CA176624 · United States
NCI NIH HHS · R01 CA176624 · United States
NIAID NIH HHS · AI105887 · United States
NIAID NIH HHS · R01 AI105887 · United States
NINDS NIH HHS · NS064599 · United States
NIAID NIH HHS · R00 AI110649 · United States
NIAID NIH HHS · AI101407 · United States
NIAID NIH HHS · R37 AI105887 · United States
NIAID NIH HHS · R21 AI094089 · United States
External Links
PubMed source DOI: 10.1038/ni.3365 PMC Full Text View journal details
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