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

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

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.

Publication types

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

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Endoplasmic Reticulum / metabolism*
  • Humans
  • Intracellular Membranes / metabolism
  • Lymphocyte Activation / immunology
  • Mice, Knockout
  • Mice, Transgenic
  • Multiple Sclerosis / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Th1 Cells / immunology
  • Th17 Cells / immunology
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / immunology*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Cdkn1b protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p27
  • SYVN1 protein, human
  • Syvn1 protein, mouse
  • Ubiquitin-Protein Ligases