title: Ubiquitin ligase MARCH 8 cooperates with CD83 to control surface MHC II expression in thymic epithelium and CD4 T cell selection.
abstract: Major histocompatibility complex class II (MHC II) expression is tightly regulated, being subjected to cell type-specific mechanisms that closely control its levels at the cell surface. Ubiquitination by the E3 ubiquitin ligase MARCH 1 regulates MHC II expression in dendritic cells and B cells. In this study, we demonstrate that the related ligase MARCH 8 is responsible for regulating surface MHC II in thymic epithelial cells (TECs). March8(-/-) mice have elevated MHC II at the surface of cortical TECs and autoimmune regulator (AIRE)(-) medullary TECs (mTECs), but not AIRE(+) mTECs. Despite this, thymic and splenic CD4(+) T cell numbers and repertoires remained unaltered in March8(-/-) mice. Notably, the ubiquitination of MHC II by MARCH 8 is controlled by CD83. Mice expressing a mutated form of CD83 (Cd83(anu/anu) mice) have impaired CD4(+) T cell selection, but deleting March8 in Cd83(anu/anu) mice restored CD4(+) T cell selection to normal levels. Therefore, orchestrated regulation of MHC II surface expression in TECs by MARCH 8 and CD83 plays a major role in CD4(+) T cell selection. Our results also highlight the specialized use of ubiquitinating machinery in distinct antigen-presenting cell types, with important functional consequences and implications for therapeutic manipulation.
authors: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors: Haiyin
authors: 0000-0003-3103-6949
authors: H
authors: Liu
authors: Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors: Reema
authors: 0000-0002-8100-9300
authors: R
authors: Jain
authors: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria 3010, Australia Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
authors: Jing
authors: J
authors: Guan
authors: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors: Vivian
authors: 0000-0002-1389-1514
authors: V
authors: Vuong
authors: Laboratory of Integrative Infection Immunity, Showa Pharmaceutical University, Machida, Tokyo 194-0042, Japan Department of Microbiology, Hyogo College of Medicine, Hyogo 663-8131, Japan.
authors: Satoshi
authors: 0000-0002-4447-8853
authors: S
authors: Ishido
authors: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria 3010, Australia Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
authors: Nicole L
authors: NL
authors: La Gruta
authors: Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors: Daniel H
authors: DH
authors: Gray
authors: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria 3010, Australia jmintern@unimelb.edu.au j.villadangos@unimelb.edu.au.
authors: Jose A
authors: 0000-0001-6771-8891
authors: JA
authors: Villadangos
authors: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia jmintern@unimelb.edu.au j.villadangos@unimelb.edu.au.
authors: Justine D
authors: JD
authors: Mintern
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D007136:Immunoglobulins / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013950:Thymus Gland / Q000000981:diagnostic imaging* / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D054875:Ubiquitination; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D000949:Histocompatibility Antigens Class II; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D044767:Ubiquitin-Protein Ligases; D000097802:CD83 Antigen; C559132:March8 protein, mouse