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Ubc13 maintains the suppressive function of regulatory T cells and prevents their conversion into effector-like T cells

Abstract

The maintenance of immune homeostasis requires regulatory T cells (Treg cells). Here we found that Treg cell–specific ablation of Ubc13, a Lys63 (K63)-specific ubiquitin-conjugating enzyme, caused aberrant T cell activation and autoimmunity. Although Ubc13 deficiency did not affect the survival of Treg cells or expression of the transcription factor Foxp3, it impaired the in vivo suppressive function of Treg cells and rendered them sensitive to the acquisition of T helper type 1 (TH1) cell– and interleukin 17 (IL-17)-producing helper T (TH17) cell–like effector phenotypes. This function of Ubc13 involved its downstream target, the kinase IKK. The Ubc13-IKK signaling axis controlled the expression of specific Treg cell effector molecules, including IL-10 and SOCS1. Collectively, our findings suggest that the Ubc13-IKK signaling axis regulates the molecular program that maintains Treg cell function and prevents Treg cells from acquiring inflammatory phenotypes.

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Figure 1: Treg cell–specific ablation of Ubc13 causes systemic autoimmunity.
Figure 2: Treg cell–specific ablation of Ubc13 impairs T-cell homeostasis.
Figure 3: Ubc13 is dispensable for the homeostasis and in vitro suppressive activity of Treg cells.
Figure 4: Treg cell–specific ablation of Ubc13 impairs the in vivo immunosuppressive function of Treg cells.
Figure 5: Ubc13-deficient Treg cells are sensitive to lymphopenic and inflammatory conditions for the acquisition of effector functions.
Figure 6: The Treg cell–specific function of Ubc13 involves its downstream target, IKK.
Figure 7: Ubc13 is dispensable for the expression of Treg cell signature genes but regulates the expression Socs1 and Il10.
Figure 8: Synergistic activation of the Socs1 promoter by IKK2 and STAT3 via a STAT–NF-κB composite site.
Figure 9: A SOCS1 mimetic peptide partially 'rescues' the functional defect of Ubc13-deficient Treg cells both in vitro and in vivo.

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Acknowledgements

We thank M. Karin (University of California, San Diego) for the IKK2(CA) expression vector; T. Kishimoto (Osaka University) for the mouse Socs1-luc reporter; and personnel from the flow cytometry, DNA analysis, and histology core facilities at MD Anderson Cancer Center for technical assistance. This work is supported by the US National Institutes of Health (AI057555, AI064639 and GM84459) and the G.S. Hogan Gastrointestinal Cancer Research Fund.

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J.-H.C. designed and did the research, prepared the figures, and wrote part of the manuscript; Y.X. did the luciferase assays; X.Z. provided technical help for adoptive transfer; H.H. did the Ubc13 immunoblot analysis; J.J. constructed the mutant Socs1 luciferase plasmid; J.Y., X.C. and X.W. contributed to the generation of mouse models; H.M.J., S.A. and M.P. contributed reagents; and S.-C.S. designed the research and wrote the manuscript.

Corresponding author

Correspondence to Shao-Cong Sun.

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The authors declare no competing financial interests.

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Chang, JH., Xiao, Y., Hu, H. et al. Ubc13 maintains the suppressive function of regulatory T cells and prevents their conversion into effector-like T cells. Nat Immunol 13, 481–490 (2012). https://doi.org/10.1038/ni.2267

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