Abstract
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 serine/threonine kinase 4 (Stk4), leading to the formation of an Stk4-NF-?B 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 Treg cells, either alone or in combination with its homolog Stk3, precipitated a fatal autoimmune lymphoproliferative disease in mice characterized by decreased Treg cell p65 expression and nuclear translocation, impaired NF-?B p65-Foxp3 complex formation, and defective Treg cell activation. In an adoptive immunotherapy model, overexpression of p65 or the phosphomimetic Foxp3S418E in Stk3/4-deficient Treg cells ameliorated their immune regulatory defects. Our studies identify Stk4 as an essential TCR-responsive regulator of p65-Foxp3-dependent transcription that promotes Treg cell-mediated immune tolerance.
Anno
2022
Autori IAC
Tipo pubblicazione
Altri Autori
Y. Cui, M. Benamar, K. SchmitzAbe, V.PoondiKrishnan, Q. Chen, B.E. Jugder, B. Fatou, J. Fong, Y. Zhong, S. Mehta, A. Buyanbat, B. S. Eklioglu, E. Karabiber, S. Baris, A. Kiykim, S. Keles, E. StephenVictor, C. Angelini, L.M. Charbonnier, T. A. Chatila
Editore
American Association for the Advancement of Science
Rivista
Science immunology