Regulation of T Cell Differentiation and Allergic Responses by the E3 Ubiquitin Ligase Itch
Itch is an E3 ubiquitin ligase that is originally identified by genetic analysis of a mutant mouse with aberrant immunological phenotypes and constant itching in the skin. Itch–/– T cells are biased toward the differentiation of T helper type 2 cells with augmented interleukin-4 cytokine production and serum IgE level. One of the mechanisms for Itch E3 ligase to regulate T cell responses is the induction of T cell anergy in which T cells become unresponsive upon restimulation. However, the detailed mechanisms underlying Itch-mediated protein ubiquitination and allergic responses remain to be investigated. Here we provide evidence that Itch is involved in the regulation of transforming growth factor (TGF)-β signaling in naïve T cells and TGF-β-induced expression of the transcription factor Foxp3, a master regulator in regulatory T cells. Itch promotes ubiquitin conjugation to TGF-β inducible early gene 1 product (TIEG1). Moreover, monoubiquitinated TIEG1 positively modulates the transcription of Foxp3 gene. The results suggest a novel mechanism by which Itch regulates regulatory T cells and subsequent allergic responses.
KeywordsProtein Ubiquitination Foxp3 Expression Tolerance Induction Foxp3 Gene Cell Anergy
The author thanks the contributions from postdoctoral fellows trained in this laboratory and from outside collaborators. The work on Itch project is supported by NIH funding.