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.
Bibliographical noteFunding 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.
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All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)