A Stk4 -Foxp3-P65 Transcriptional Complex Promotes Treg Cell Activation and Homeostasis

The molecular programs involved in regulatory T (Treg) cell activation and homeostasis remain incompletely understood. Here we show that T cell receptor (TCR) signaling in Treg cells induces the nuclear translocation of Stk4, leading to the formation of a Stk4/NFkb p65/Foxp3 complex that regulates Foxp3 and p65-dependent transcriptional programs. The formation of this complex was stabilized by Stk4-dependent phosphorylation of Foxp3 serine 418. Stk4 deficiency in Treg cells, either alone or in synergy with that of its homologue Stk3, precipitated a fatal autoimmune lymphoproliferative disease characterized by decreased Treg cell p65 expression and nuclear translocation, impaired NF-kb p65/Foxp3 complex formation and defective Treg cell activation. In an adoptive immunotherapy model, over-expression of p65 or the phosphomimetic Foxp3S418E in Stk3/4-deficient Treg cells ameliorated their immune regulatory defects. Our studies identify Stk3/4 as an essential TCR-responsive regulator of p65-Foxp3-dependent transcription that promotes Treg cell-mediated immune tolerance.