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

Yu Mi Oh, Hyung Bae Park, Jae Hun Shin, Ji Eun Lee, Ha Young Park, Dhong Hyo Kho, Jun Sung Lee, Heonsik Choi, Tomohiko Okuda, Koichi Kokame, Toshiyuki Miyata, In-Hoo Kim, Seung Hoon Lee, Ronald H. Schwartz and Kyungho Choi ()
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Yu Mi Oh: Seoul National University College of Medicine
Hyung Bae Park: Seoul National University College of Medicine
Jae Hun Shin: Specific Organs Cancer Branch, Research Institute National Cancer Center
Ji Eun Lee: Seoul National University College of Medicine
Ha Young Park: Seoul National University College of Medicine
Dhong Hyo Kho: Specific Organs Cancer Branch, Research Institute National Cancer Center
Jun Sung Lee: Specific Organs Cancer Branch, Research Institute National Cancer Center
Heonsik Choi: Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Tomohiko Okuda: National Cerebral and Cardiovascular Center
Koichi Kokame: National Cerebral and Cardiovascular Center
Toshiyuki Miyata: National Cerebral and Cardiovascular Center
In-Hoo Kim: Molecular Imaging and Therapy Branch, Research Institute National Cancer Center
Seung Hoon Lee: Specific Organs Cancer Branch, Research Institute National Cancer Center
Ronald H. Schwartz: Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Kyungho Choi: Seoul National University College of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9698

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