Ubiquitin ligase MARCH 8 cooperates with CD83 to control surface MHC II expression in thymic epithelium and CD4 T cell selection

被引:54
作者
Liu, Haiyin [1 ]
Jain, Reema [2 ,4 ]
Guan, Jing [3 ,5 ,6 ]
Vuong, Vivian [1 ]
Ishido, Satoshi [7 ,8 ]
La Gruta, Nicole L. [3 ,5 ,6 ]
Gray, Daniel H. [2 ,4 ]
Villadangos, Jose A. [1 ,3 ]
Mintern, Justine D. [1 ]
机构
[1] Univ Melbourne, Mol Sci & Biotechnol Inst Bio21, Dept Biochem & Mol Biol, Parkville, Vic 3010, Australia
[2] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010, Australia
[3] Univ Melbourne, Dept Microbiol & Immunol, Peter Doherty Inst Infect & Immun, Parkville, Vic 3010, Australia
[4] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia
[5] Monash Univ, Infect & Immun Program, Clayton, Vic 3800, Australia
[6] Monash Univ, Biomed Discovery Inst, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia
[7] Showa Pharmaceut Univ, Lab Integrat Infect Immun, Machida, Tokyo 1940042, Japan
[8] Hyogo Coll Med, Dept Microbiol, Nishinomiya, Hyogo 6638131, Japan
基金
澳大利亚国家健康与医学研究理事会; 英国医学研究理事会; 澳大利亚研究理事会;
关键词
DENDRITIC CELLS; ANTIGEN PRESENTATION; B-CELLS; DEGRADATION; REPERTOIRE; MEMBRANE; PEPTIDES;
D O I
10.1084/jem.20160312
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 MAR CH 1 regulates MHC II expression in dendritic cells and B cells. In this study, we demonstrate that the related ligase MAR CH 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 MAR CH 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 MAR CH 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.
引用
收藏
页码:1695 / 1703
页数:9
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