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

doi:10.1016/j.celrep.2019.02.087

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

Cell Rep. 2019 Mar 26;26(13):3600-3612.e6. doi: 10.1016/j.celrep.2019.02.087.

Authors

Affiliations

¹ Center for Molecular Medicine, Division of Pediatrics, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands.
² Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Ashworth Laboratories, Edinburgh, UK.
³ ENT Department, Affiliated Eye and ENT Hospital, Fudan University, Shanghai, China.
⁴ Department of Otolaryngology, The Children's Hospital of Chongqing Medical University, 136 Zhongshaner Road, Chongqing 400014, China.
⁵ Center for Molecular Medicine, Division of Pediatrics, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands; Regenerative Medicine Center, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands.
⁶ Immunology Program, Howard Hughes Medical Institute, and Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁷ Hubrecht Institute, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands.
⁸ Proteins at Work, UMC Utrecht, Utrecht, the Netherlands.
⁹ Immunology and Hematopoiesis Division, Department of Oncology, Bloomberg-Kimmel Institute, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ ENT Department, Affiliated Eye and ENT Hospital, Fudan University, Shanghai, China. Electronic address: allergyli@163.com.
¹¹ Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Ashworth Laboratories, Edinburgh, UK. Electronic address: dietmar.zaiss@ed.uk.ac.
¹² Center for Molecular Medicine, Division of Pediatrics, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands; Regenerative Medicine Center, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands. Electronic address: pcoffer@umcutrecht.nl.

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.

Keywords: Foxp3; NLK; TCR; immune tolerance; phosphorylation; regulatory T cell; ubiquitination.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Female
Forkhead Transcription Factors / metabolism*
HEK293 Cells
Humans
Immune Tolerance*
Inflammation / immunology
MAP Kinase Kinase Kinases / metabolism
Male
Mice
Mice, Inbred C57BL
Phosphorylation
Protein Stability
Signal Transduction
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / metabolism

Substances

FOXP3 protein, human
Forkhead Transcription Factors
MAP Kinase Kinase Kinases
MAP kinase kinase kinase 7

Abstract

Publication types

MeSH terms

Substances

Grants and funding