T cell activation is subject to tight regulation to avoid inappropriate responses to self antigens. Here we show that genetic deficiency in the ubiquitin ligase Peli1 caused hyperactivation of T cells and rendered T cells refractory to suppression by regulatory T cells and transforming growth factor-β (TGF-β). As a result, Peli1-deficient mice spontaneously developed autoimmunity characterized by multiorgan inflammation and autoantibody production. Peli1 deficiency resulted in the nuclear accumulation of c-Rel, a member of the NF-κB family of transcription factors with pivotal roles in T cell activation. Peli1 negatively regulated c-Rel by mediating its Lys48 (K48) ubiquitination. Our results identify Peli1 as a critical factor in the maintenance of peripheral T cell tolerance and demonstrate a previously unknown mechanism of c-Rel regulation.
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We thank the Texas Institute for Genomic Medicine for Peli1−/− mice; S.H. Park (Sungkyunkwan University) for hemagglutinin-tagged Peli1 and Peli1ΔC expression vectors; R. Beyaert (Ghent University) for E-tag–Peli1; X. Qin (MD Anderson Cancer Center) for lentiviral packaging vectors; Z. Chen (University of Texas Southwestern Medical Center) for the hemagglutinin-tagged K48R and K63R ubiquitin mutants; and K. Dwyer, K. Ramirez and K. Ackin from the flow cytometry core facility and S. Mudd from the histology core facility of MD Anderson Cancer Center for technical assistance. Supported by the US National Institutes of Health (AI057555, AI064639, GM84459 and GM84459-S1 to S.-C.S. and T32CA009598 to G.C.B).
The authors declare no competing financial interests.
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