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Nat Commun. 2016 Jul 15;7:12073. doi: 10.1038/ncomms12073.

The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity.

Author information

1
Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Chicago, Illinois 60611, USA.
2
Allergy Center, Department of Otolaryngology-Head and Neck Surgery, Affiliated Eye and ENT Hospital, Fudan University, Shanghai 200031, China.
3
Robert H. Lurie Comprehensive Cancer Center, Department of Medicine-Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
4
Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China.
5
Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
6
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizon 85721, USA.
7
Department of Biochemistry, School of Life Science and Medicine, Dalian University of Technology, 2 Linggong Road, Dalian 116024, China.
8
Guangdong Provincial Engineering Research Center for Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.

Abstract

Identification of positive regulators of T-cell immunity induced during autoimmune diseases is critical for developing novel therapies. The endoplasmic reticulum resident ubiquitin ligase Hrd1 has recently emerged as a critical regulator of dendritic cell antigen presentation, but its role in T-cell immunity is unknown. Here we show that genetic deletion of Hrd1 in mice inhibits T-cell proliferation, production of IL-2, and differentiation of Th1 and Th17 cells, and consequently protects mice from experimental autoimmune encephalomyelitis. Hrd1 facilitates T-cell proliferation by the destruction of cyclin-dependent kinase inhibitor p27(kip1), and deletion of p27(kip1) in Hrd1-null T-cells rescues proliferative capacity but not the production of cytokines, including IL-2, IFN-γ and IL-17. T-cell expression of Hrd1 is higher in patients with multiple sclerosis than in healthy individuals, and knockdown of Hrd1 in human CD4(+) T cells inhibits activation and differentiation to Th1 and Th17 cells. Our study identifies Hrd1 as a previously unappreciated positive regulator of T cells and implies that Hrd1 is a potential therapeutic target for autoimmune diseases.

PMID:
27417417
PMCID:
PMC4947160
DOI:
10.1038/ncomms12073
[Indexed for MEDLINE]
Free PMC Article

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