UBL3 Participates in the Early Stages of CD83‐Dependent CD4 + T Cell Selection

ABSTRACT CD83 is critical for CD4 + T cell selection. It regulates MHC II ubiquitination and turnover at the surface of thymic epithelial cells (TECs). The role of UBL3, a recently identified adaptor molecule for MHC II ubiquitination, is unknown in thymic selection. Here we demonstrate that UBL3 regulates MHC II in TECs and participates in CD4 + T cell selection. Deleting UBL3 in CD83 loss‐of‐function mice ( Cd83 anu/anu Ubl3 −/− ) increases MHC II on the surface of Cd83 anu/anu TECs. This increase in surface MHC II correlates with increased positive selection of CD4 + T cells. Analysis of Cd83 anu/anu and Cd83 anu/anu Ubl3 −/− mice identifies the CD4 + CD8 low CD69 + stage of positive selection as the origin of the CD4 + T cell selection defect in Cd83 anu/anu mice. This stage of CD4 + T cell positive selection is also impacted by UBL3. The positive selection defect in the absence of CD83 also manifests as alterations in CCR7 + CD4 single‐positive (SP) thymocytes. At the later stages of CD4 + T cell development, a role for UBL3 is no longer detected. In summary, through in‐depth phenotyping of thymocyte populations, a role for CD83 and UBL3 in regulating the early stages of CD4 + T cell positive selection has been identified.