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

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.