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The ubiquitin ligase Peli1 negatively regulates T cell activation and prevents autoimmunity

Nature Immunology volume 12, pages 1002–1009 (2011)Cite this article

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Abstract

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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Figure 1: Peli1-deficient T cells are hyper-responsive to TCR and CD28 signals.
Figure 2: A cell-autologous role for Peli1 in regulating T cell homeostasis in vivo.
Figure 3: Peli1 deficiency renders naive T cells refractory to suppression by Treg cells and TGF-β.
Figure 4: Spontaneous development of signs of autoimmune disease by Peli1−/− mice.
Figure 5: Peli1 deficiency causes hyperactivation of late-phase NF-κB.
Figure 6: Peli1 negatively regulates c-Rel.
Figure 7: Peli1 induces ubiquitination of c-Rel.

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Change history

  • 20 September 2011

    In the version of this article initially published, in the Online Methods subsection "Analysis of TCR-proximal signaling," the catalog number for goat antibody to hamster immunoglobulin was incorrect. The correct number is 127-005-160. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

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).

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Author notes

  1. Wei Jin

    Present address: Present address: Howard Hughes Medical Institute and Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.,

  2. Mikyoung Chang and Wei Jin: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Mikyoung Chang, Wei Jin, Jae-Hoon Chang, Yichuan Xiao, George C Brittain, Jiayi Yu, Xiaofei Zhou, Yi-Hong Wang, Xuhong Cheng & Shao-Cong Sun

  2. Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, USA

    Pingwei Li

  3. Immunology Laboratory of Physician Scientists, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Brian A Rabinovich

  4. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Patrick Hwu

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Contributions

M.C. and W.J. designed and did the research and prepared the figures; J.-H.C. did the in vitro Treg cell assays and OVA tolerance assays; Y.X., J.Y. and X.Z. did the EAE experiment; G.C.B. did the experiments with knockdown and overexpression of Peli1 in EL4 cells; Y.-H.W. did the histology and immunohistochemistry; X.C. constructed Peli1 expression vectors; P.L., B.A.R. and P.H. contributed reagents; and S.-C.S. designed the research and wrote the manuscript.

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Correspondence to Shao-Cong Sun.

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Chang, M., Jin, W., Chang, JH. et al. The ubiquitin ligase Peli1 negatively regulates T cell activation and prevents autoimmunity. Nat Immunol 12, 1002–1009 (2011). https://doi.org/10.1038/ni.2090

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