A Stk4-Foxp3–NF-κB p65 transcriptional complex promotes T <sub>reg</sub> cell activation and homeostasis
Ye Cui, Mehdi Benamar, Klaus Schmitz‐Abe, Varsha Poondi Krishnan, Qian Chen, Bat‐Erdene Jugder, Benoit Fatou, Jason Fong, Yuelin Zhong, Stuti Mehta, Altantsetseg Buyanbat, Beray Selver Eklioğlu, Esra Karabıber, Safa Barış, Ayça Kıykım, Sevgi Keleş, Emmanuel Stephen‐Victor, Claudia Angelini, Louis‐Marie Charbonnier, Talal A. Chatila
Abstract
The molecular programs involved in regulatory T (T reg ) cell activation and homeostasis remain incompletely understood. Here, we show that T cell receptor (TCR) signaling in T reg cells induces the nuclear translocation of serine/threonine kinase 4 (Stk4), leading to the formation of an Stk4–NF-κB p65–Foxp3 complex that regulates Foxp3- and p65-dependent transcriptional programs. This complex was stabilized by Stk4-dependent phosphorylation of Foxp3 on serine-418. Stk4 deficiency in T reg cells, either alone or in combination with its homolog Stk3, precipitated a fatal autoimmune lymphoproliferative disease in mice characterized by decreased T reg cell p65 expression and nuclear translocation, impaired NF-κB p65–Foxp3 complex formation, and defective T reg cell activation. In an adoptive immunotherapy model, overexpression of p65 or the phosphomimetic Foxp3 S418E in Stk3/4-deficient T reg cells ameliorated their immune regulatory defects. Our studies identify Stk4 as an essential TCR-responsive regulator of p65-Foxp3–dependent transcription that promotes T reg cell–mediated immune tolerance.