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

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.