Peli1 negatively regulates T-cell activation and prevents autoimmunity

T-cell activation is subject to tight regulation to avoid inappropriate responses against self-antigens. Here we show that genetic deficiency in an ubiquitin ligase, Peli1, causes hyper activation of T cells and renders T cells refractory to suppression by T regulatory cells and transforming growth factor (TGF)-β. As a result, Peli1 knockout mice spontaneously develop autoimmunity, characterized by multiorgan inflammation and autoantibody production. Peli1 deficiency results in accumulation of nuclear c-Rel, a member of the NF-κB family of transcription factors with pivotal roles in T-cell activation. Peli1 negatively regulates c-Rel by mediating its K48 ubiquitination. These results identify Peli1 as a critical factor in the maintenance of peripheral T-cell tolerance and reveal a novel mechanism of c-Rel regulation.