title: E3 Ubiquitin Ligase Cbl-b Regulates Thymic-Derived CD4+CD25+ Regulatory T Cell Development by Targeting Foxp3 for Ubiquitination.
abstract: CD28 costimulation is essential for the development of thymic-derived CD4(+)CD25(+)Foxp3(+) regulatory T cells ("tTregs"). E3 ubiquitin ligase Cbl-b has been shown to regulate CD28 dependence of T cell activation. In this paper, we report that the loss of Cbl-b partially but significantly rescues the defective development of tTregs in Cd28(-/-) mice. This partial rescue is independent of IL-2. Mechanistically, Cbl-b binds to Foxp3 upon TCR stimulation and, together with Stub1, targets Foxp3 for ubiquitination and subsequently degradation in the proteasome. As Cbl-b self-ubiquitination and proteasomal degradation is impaired in Cd28(-/-) T cells, the defective development of tTregs in Cd28(-/-) mice may in part be due to increased Foxp3 ubiquitination and degradation targeted by Stub1 and Cbl-b. Treating Cd28(-/-) mice with a proteasome inhibitor completely rescues defective tTreg development in these mice. Therefore, Cbl-b, together with Stub1, ubiquitinate Foxp3, and regulate tTreg development.
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210;
authors.forename: Yixia
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210;
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210; Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 60637; and.
authors.forename: Guilin
authors.initials: G
authors.lastname: Qiao
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210;
authors.forename: Mark
authors.initials: M
authors.lastname: Zucker
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia.
authors.forename: Wallace Y
authors.initials: WY
authors.lastname: Langdon
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210; Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 60637; and jian.zhang@osumc.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology*; D000818:Animals; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050721:Proto-Oncogene Proteins c-cbl / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000276:immunology / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C118387:Cblb protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050721:Proto-Oncogene Proteins c-cbl; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases