A Stk4-Foxp3-NF-κB p65 transcriptional complex promotes T_reg cell activation and homeostasis

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.