Ndrg1 is a T-cell clonal anergy factor negatively regulated by CD28 costimulation and interleukin-2.
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.
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, Korea.|Specific Organs Cancer Branch, Research Institute National Cancer Center, Gyeonggi-do 410-769, Korea.
Yu Mi
YM
Oh
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, Korea.|Hematologic Malignancy Branch, Research Institute National Cancer Center, Gyeonggi-do 410-769, Korea.
Hyung Bae
HB
Park
Specific Organs Cancer Branch, Research Institute National Cancer Center, Gyeonggi-do 410-769, Korea.
Jae Hun
JH
Shin
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, Korea.|Specific Organs Cancer Branch, Research Institute National Cancer Center, Gyeonggi-do 410-769, Korea.
Ji Eun
JE
Lee
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, Korea.
Ha Young
HY
Park
Specific Organs Cancer Branch, Research Institute National Cancer Center, Gyeonggi-do 410-769, Korea.
Dhong Hyo
DH
Kho
Specific Organs Cancer Branch, Research Institute National Cancer Center, Gyeonggi-do 410-769, Korea.
Jun Sung
JS
Lee
Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Heonsik
H
Choi
Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Osaka 565-8565, Japan.
Tomohiko
T
Okuda
Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Osaka 565-8565, Japan.
Koichi
K
Kokame
Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Osaka 565-8565, Japan.
Toshiyuki
T
Miyata
Molecular Imaging and Therapy Branch, Research Institute National Cancer Center, Gyeonggi-do 410-769, Korea.
In-Hoo
IH
Kim
Specific Organs Cancer Branch, Research Institute National Cancer Center, Gyeonggi-do 410-769, Korea.
Seung Hoon
SH
Lee
Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Ronald H
RH
Schwartz
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, Korea.|Specific Organs Cancer Branch, Research Institute National Cancer Center, Gyeonggi-do 410-769, Korea.
Kyungho
K
Choi
D000818:Animals; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000276:immunology; D017635:Clonal Anergy; D015536:Down-Regulation; D051767:Early Growth Response Protein 2 / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology*; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D018106:CD28 Antigens; D018797:Cell Cycle Proteins; D051767:Early Growth Response Protein 2; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C497327:Egr2 protein, mouse