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

Summary: The Foxp3 transcription factor is a crucial determinant of both regulatory T (TREG) 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 TREG cells can be regulated by a TGF-β activated kinase 1 (TAK1)-Nemo-like kinase (NLK) signaling pathway. NLK interacts and phosphorylates Foxp3 in TREG cells, resulting in the stabilization of protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase. Conditional TREG cell NLK-knockout (NLKΔTREG) results in decreased TREG cell-mediated immunosuppression in vivo, and NLK-deficient TREG 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 TREG cell suppressive function. : The maintenance of Foxp3 expression is critical for correct TREG 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 TREG cell suppressive function. Keywords: Foxp3, phosphorylation, regulatory T cell, NLK, TCR, ubiquitination, immune tolerance