title: Regulation of proximal T cell receptor signaling and tolerance induction by deubiquitinase Usp9X.
abstract: The T cell hyperproliferation and autoimmune phenotypes that manifest in mice lacking E3 ubiquitin ligases such as Cbl, ITCH, or GRAIL highlight the importance of ubiquitination for the maintenance of peripheral T cell tolerance. Less is known, however, about the deubiquitinating enzymes that regulate T cell proliferation and effector function. Here, we define a cell intrinsic role for the deubiquitinase Usp9X during proximal TCR signaling. Usp9X-deficient T cells were hypoproliferative, yet mice with T cell-specific Usp9x deletion had elevated numbers of antigen-experienced T cells and expanded PD-1 and OX40-expressing populations consistent with immune hyperactivity. Aged Usp9x KO mice developed lupus-like autoimmunity and lymphoproliferative disease, indicating that ubiquitin ligases and deubiquitinases maintain the delicate balance between effective immunity and self-tolerance.
authors.affiliation: Department of Physiological Chemistry, Department of Pathology, Department of Immunology, Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Edwina
authors.initials: E
authors.lastname: Naik
authors.affiliation: Department of Physiological Chemistry, Department of Pathology, Department of Immunology, Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Webster
authors.affiliation: Department of Physiological Chemistry, Department of Pathology, Department of Immunology, Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Jason
authors.initials: J
authors.lastname: DeVoss
authors.affiliation: Department of Physiological Chemistry, Department of Pathology, Department of Immunology, Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Physiological Chemistry, Department of Pathology, Department of Immunology, Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Rowena
authors.initials: R
authors.lastname: Suriben
authors.affiliation: Department of Physiological Chemistry, Department of Pathology, Department of Immunology, Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, CA 94080 dixit@gene.com.
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics*; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation; D017931:DNA Primers / Q000235:genetics; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D008214:Lymphocytes / Q000378:metabolism; D008232:Lymphoproliferative Disorders / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D043222:Ubiquitin Thiolesterase
chemical_list: D017931:DNA Primers; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D010450:Endopeptidases; D043222:Ubiquitin Thiolesterase; C404328:Usp9x protein, mouse; D002118:Calcium