| First Author | Cui Y | Year | 2022 |
| Journal | Sci Immunol | Volume | 7 |
| Issue | 75 | Pages | eabl8357 |
| PubMed ID | 36149942 | Mgi Jnum | J:339188 |
| Mgi Id | MGI:7517258 | Doi | 10.1126/sciimmunol.abl8357 |
| Citation | Cui Y, et al. (2022) A Stk4-Foxp3-NF-kappaB p65 transcriptional complex promotes T(reg) cell activation and homeostasis. Sci Immunol 7(75):eabl8357 |
| abstractText | 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-kappaB 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-kappaB 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. |
