Venuprasad, K.

Transforming growth factor (TGF)‐b signaling in naïve T cells induces expression of transcription factor Foxp3, a master regulator in the regulatory T cells (Tregs). However, the molecular mechanisms leading to Foxp3 induction remain unclear. Here we show that Itch−/− T cells are resistant to TGF‐b treatment with reduced Foxp3 expression. The E3 ubiquitin ligase Itch associates with and promotes ubiquitin conjugation to TGF‐b inducible early gene1 product (TIEG1). More importantly, Itch cooperates with TIEG1 to induce Foxp3 expression, which is reversed by TIEG1 deficiency. Functionally TGF‐b‐converted Tregs generated from TIEG1−/− mice are unable to inhibit naïve T cell proliferation in vitro and suppress airway inflammation in vivo. The results suggest an ubiquitin‐dependent non‐proteolytic pathway that is critical for Foxp3 expression and regulation of allergic responses.

Abstract Earlier, we demonstrated the essential role of Kruppel-like transcription factor, TIEG1, in TGF-β–induced regulatory T cell (Treg) development. In this article, we demonstrate that IL-6, which promotes Th17 development, abrogated TIEG1 nuclear translocation and inhibited TGF-β–induced Treg development. Tyrosine kinase Tyk2-mediated phosphorylation of TIEG1 at Tyr179 promoted noncanonical K-27–linked polyubiquitination, which inhibited TIEG1 nuclear translocation. To test the role of TIEG1-regulated Treg/Th17 development in antitumor immunity, we analyzed TRAMP-C2 tumor growth in TIEG1−/− mice. The defective Treg development and elevated Th17 response resulted in enhanced immune reactivity in the tumor and inhibition of TRAMP-C2 tumor growth in TIEG1−/− mice. Thus, our results uncovered a novel regulatory mechanism that modulates Tregs and may regulate tumor progression.