2. Academic Validation
  3. Ndrg1 is a T-cell clonal anergy factor negatively regulated by CD28 costimulation and interleukin-2

Ndrg1 is a T-cell clonal anergy factor negatively regulated by CD28 costimulation and interleukin-2

  • Nat Commun. 2015 Oct 28:6:8698. doi: 10.1038/ncomms9698.
Yu Mi Oh 1 2 3,  Hyung Bae Park 1 2 4,  Jae Hun Shin 3,  Ji Eun Lee 1 2 3,  Ha Young Park 1 2,  Dhong Hyo Kho 3,  Jun Sung Lee 3,  Heonsik Choi 5,  Tomohiko Okuda 6,  Koichi Kokame 6,  Toshiyuki Miyata 6,  In-Hoo Kim 7,  Seung Hoon Lee 3,  Ronald H Schwartz 5,  Kyungho Choi 1 2 3
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, Korea.
  • 2 Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, Korea.
  • 3 Specific Organs Cancer Branch, Research Institute National Cancer Center, Gyeonggi-do 410-769, Korea.
  • 4 Hematologic Malignancy Branch, Research Institute National Cancer Center, Gyeonggi-do 410-769, Korea.
  • 5 Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • 6 Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Osaka 565-8565, Japan.
  • 7 Molecular Imaging and Therapy Branch, Research Institute National Cancer Center, Gyeonggi-do 410-769, Korea.
PMID: 26507712 DOI: 10.1038/ncomms9698
Abstract

Induction of T-cell clonal anergy involves serial activation of transcription factors, including NFAT and Egr2/3. However, downstream effector mechanisms of these transcription factors are not fully understood yet. Here we identify Ndrg1 as an anergy factor induced by Egr2. Ndrg1 is upregulated by anergic signalling and maintained at high levels in resting anergic T cells. Overexpression of Ndrg1 mimics the anergic state and knockout of the gene prevents anergy induction. Interestingly, Ndrg1 is phosphorylated and degraded by CD28 signalling in a proteasome-dependent manner, explaining the costimulation dependence of anergy prevention. Similarly, IL-2 treatment of anergic T cells, under conditions that lead to the reversal of anergy, also induces Ndrg1 phosphorylation and degradation. Finally, older Ndrg1-deficient mice show T-cell hyperresponsiveness and Ndrg1-deficient T cells aggravate inducible autoimmune inflammation. Thus, Ndrg1 contributes to the maintenance of clonal anergy and inhibition of T-cell-mediated inflammation.

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