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)-beta signaling in naive T cells and TGF-beta-induced expression of the transcription factor Foxp3, a master regulator in regulatory T cells. Itch promotes ubiquitin conjugation to TGF-beta 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.