Abstract
FOXP3+ Regulatory T (Treg) cells play a key role in the maintenance of immune homeostasis and tolerance. Disruption of Foxp3 expression results in the generation of instable Treg cells and acquisition of effector T-cell-like function. Here we report that the E3 deubiquitinase USP21 prevents the depletion of FOXP3 at the protein level and restricts the generation of T-helper-1-like Treg cells. Mice depleted of Usp21 specifically in Treg cells display immune disorders characterized by spontaneous T-cell activation and excessive T-helper type 1 (Th1) skewing of Treg cells into Th1-like Treg cells. USP21 stabilizes FOXP3 protein by mediating its deubiquitination and maintains the expression of Treg signature genes. Our results demonstrate how USP21 prevents FOXP3 protein depletion and controls Treg lineage stability in vivo.
Highlights
Immunology, Unit of Hematopoietic Stem Cell and Transgenic Animal Model, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China. 6 Key Laboratory of Molecular Virology and Immunology, Unit of Immune Regulation, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China. 7 Flow Cytometry Core Facility, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China. 8 Key Laboratory of Molecular Virology and Immunology, Unit of the Regulation of Immune Cell Differentiation, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China. 9 Clinical Immunology Center, Third Affiliated Hospital at Sun Yat-Sen University, Guangzhou 510630, China
We previously identified how the E3 deubiquitinase USP21 is highly induced in human CD4 þ CD25hiCD127lo Treg cells from asthma patients[24], but the in vivo function of USP21 remained unclear
We further found the loss of FOXP3 protein in USP21-DTreg cells could be prevented by the addition of proteasome inhibitor MG132 (Fig. 7d), suggesting that the ubiquitin-proteasome pathway might be involved in this process
Summary
Immunology, Unit of Hematopoietic Stem Cell and Transgenic Animal Model, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China. 6 Key Laboratory of Molecular Virology and Immunology, Unit of Immune Regulation, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China. 7 Flow Cytometry Core Facility, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China. 8 Key Laboratory of Molecular Virology and Immunology, Unit of the Regulation of Immune Cell Differentiation, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China. 9 Clinical Immunology Center, Third Affiliated Hospital at Sun Yat-Sen University, Guangzhou 510630, China. 6 Key Laboratory of Molecular Virology and Immunology, Unit of Immune Regulation, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China. 8 Key Laboratory of Molecular Virology and Immunology, Unit of the Regulation of Immune Cell Differentiation, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China. Compromised epigenetic programing at the Foxp[3] gene locus abrogates its gene transcription and facilitates the generation of exFOXP3 T cells[5,15,16,17,18] These exFOXP3 T cells may produce inflammatory cytokines that lead to the rapid onset of autoimmune diseases[5,10]. Our results show that USP21 prevents FOXP3 protein depletion and controls Treg lineage stability in vivo
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