Nemo-like Kinase Drives Foxp3 Stability and Is Critical for Maintenance of Immune Tolerance by Regulatory T Cells

Veerle Fleskens, Carlos M. Minutti, Xingmei Wu, Ping Wei, Cornelieke E.G.M. Pals, James McCrae, Saskia Hemmers, Vincent Groenewold, Harm Jan Vos, Alexander Rudensky, Fan Pan, Huabin Li, Dietmar M. Zaiss, Paul J. Coffer

Research output: Contribution to journalArticle

Abstract

The Foxp3 transcription factor is a crucial determinant of both regulatory T (T REG ) cell development and their functional maintenance. Appropriate modulation of tolerogenic immune responses therefore requires the tight regulation of Foxp3 transcriptional output, and this involves both transcriptional and post-translational regulation. Here, we show that during T cell activation, phosphorylation of Foxp3 in T REG cells can be regulated by a TGF-β activated kinase 1 (TAK1)-Nemo-like kinase (NLK) signaling pathway. NLK interacts and phosphorylates Foxp3 in T REG cells, resulting in the stabilization of protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase. Conditional T REG cell NLK-knockout (NLK ΔTREG ) results in decreased T REG cell-mediated immunosuppression in vivo, and NLK-deficient T REG cell animals develop more severe experimental autoimmune encephalomyelitis. Our data suggest a molecular mechanism, in which stimulation of TCR-mediated signaling can induce a TAK1-NLK pathway to sustain Foxp3 transcriptional activity through the stabilization of protein levels, thereby maintaining T REG cell suppressive function. The maintenance of Foxp3 expression is critical for correct T REG cell function. Fleskens et al. demonstrate a molecular mechanism in which TCR engagement can stabilize Foxp3 protein expression through TAK1-NLK-regulated phosphorylation, thereby maintaining T REG cell suppressive function.

Original languageEnglish (US)
Pages (from-to)3600-3612.e6
JournalCell Reports
Volume26
Issue number13
DOIs
StatePublished - Mar 26 2019

Keywords

  • Foxp3
  • NLK
  • TCR
  • immune tolerance
  • phosphorylation
  • regulatory T cell
  • ubiquitination

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Fleskens, V., Minutti, C. M., Wu, X., Wei, P., Pals, C. E. G. M., McCrae, J., Hemmers, S., Groenewold, V., Vos, H. J., Rudensky, A., Pan, F., Li, H., Zaiss, D. M., & Coffer, P. J. (2019). Nemo-like Kinase Drives Foxp3 Stability and Is Critical for Maintenance of Immune Tolerance by Regulatory T Cells. Cell Reports, 26(13), 3600-3612.e6. https://doi.org/10.1016/j.celrep.2019.02.087