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; Kyungho Choi

doi:10.1038/ncomms9698

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, Kyungho Choi

Integrated Sciences and Engineering Division

Research output: Contribution to journal › Article › peer-review

25 Citations (Scopus)

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.

Original language	English
Article number	8698
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9698
Publication status	Published - 2015 Oct 28

Bibliographical note

Funding Information:
We thank Chuan Chen (National Institutes of Health, Bethesda, Maryland) for assistance in maintaining and preparing the A.E7 T cell clone; Elizabeth Majane (National Institutes of Health, Bethesda, Maryland) and Dong Pyo Lim for help in breeding and maintaining the mouse lines; James Garvin and Hae Hyun Seo for technical assistance; Thérèse Commes for providing anti-Ndrg1 antibody; and Jonathan Powell (Johns Hopkins University School of Medicine, Baltimore, Maryland) for critical reading of the manuscript. We are especially grateful to Jun Yang (Laboratory of Human Retrovirology and Immunoinformatics, Leidos Biomedical Research Inc., Frederick, Maryland) for her support in the microarray experiments and analysis. This work was supported by grants from the National Cancer Center (NCC-1010090) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2013R1A2A2A01009444), Republic of Korea.

Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.

All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/ncomms9698

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@article{ff5ae06298ef41bbb995e4a2eca24028,

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

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.",

author = "Oh, {Yu Mi} and Park, {Hyung Bae} and Shin, {Jae Hun} and Lee, {Ji Eun} and Park, {Ha Young} and Kho, {Dhong Hyo} and Lee, {Jun Sung} and Heonsik Choi and Tomohiko Okuda and Koichi Kokame and Toshiyuki Miyata and Kim, {In Hoo} and Lee, {Seung Hoon} and Schwartz, {Ronald H.} and Kyungho Choi",

note = "Funding Information: We thank Chuan Chen (National Institutes of Health, Bethesda, Maryland) for assistance in maintaining and preparing the A.E7 T cell clone; Elizabeth Majane (National Institutes of Health, Bethesda, Maryland) and Dong Pyo Lim for help in breeding and maintaining the mouse lines; James Garvin and Hae Hyun Seo for technical assistance; Th{\'e}r{\`e}se Commes for providing anti-Ndrg1 antibody; and Jonathan Powell (Johns Hopkins University School of Medicine, Baltimore, Maryland) for critical reading of the manuscript. We are especially grateful to Jun Yang (Laboratory of Human Retrovirology and Immunoinformatics, Leidos Biomedical Research Inc., Frederick, Maryland) for her support in the microarray experiments and analysis. This work was supported by grants from the National Cancer Center (NCC-1010090) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2013R1A2A2A01009444), Republic of Korea. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",

year = "2015",

month = oct,

day = "28",

doi = "10.1038/ncomms9698",

language = "English",

volume = "6",

journal = "Nature communications",

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T1 - Ndrg1 is a T-cell clonal anergy factor negatively regulated by CD28 costimulation and interleukin-2

AU - Oh, Yu Mi

AU - Park, Hyung Bae

AU - Shin, Jae Hun

AU - Lee, Ji Eun

AU - Park, Ha Young

AU - Kho, Dhong Hyo

AU - Lee, Jun Sung

AU - Choi, Heonsik

AU - Okuda, Tomohiko

AU - Kokame, Koichi

AU - Miyata, Toshiyuki

AU - Kim, In Hoo

AU - Lee, Seung Hoon

AU - Schwartz, Ronald H.

AU - Choi, Kyungho

N1 - Funding Information: We thank Chuan Chen (National Institutes of Health, Bethesda, Maryland) for assistance in maintaining and preparing the A.E7 T cell clone; Elizabeth Majane (National Institutes of Health, Bethesda, Maryland) and Dong Pyo Lim for help in breeding and maintaining the mouse lines; James Garvin and Hae Hyun Seo for technical assistance; Thérèse Commes for providing anti-Ndrg1 antibody; and Jonathan Powell (Johns Hopkins University School of Medicine, Baltimore, Maryland) for critical reading of the manuscript. We are especially grateful to Jun Yang (Laboratory of Human Retrovirology and Immunoinformatics, Leidos Biomedical Research Inc., Frederick, Maryland) for her support in the microarray experiments and analysis. This work was supported by grants from the National Cancer Center (NCC-1010090) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2013R1A2A2A01009444), Republic of Korea. Publisher Copyright: © 2015 Macmillan Publishers Limited. All rights reserved.

PY - 2015/10/28

Y1 - 2015/10/28

N2 - 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.

AB - 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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JO - Nature communications

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ER -

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

Abstract

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