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


Liu, H; Jain, R; Guan, J; Vuong, V; Ishido, S; La Gruta, NL; Gray, DH; Villadangos, JA; Mintern, JD
2016-08-08
Journal of Experimental Medicine
Journal Article
213
9
1695-1703
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 (Cd83anu/anu mice) have impaired CD4+ T cell selection, but deleting March8 in Cd83anu/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.
Rockefeller Uni Press
Molecular Genetics of Cancer
10.1084/jem.20160312
27503069
Refer to article for additional funding acknowledgements
Refer to copyright notice on published article.

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Creation Date 2016-08-19 02:01:11 Last Modified 2018-07-11 09:15:30