Ubiquitination of MHC Class II by March-I Regulates Dendritic Cell Fitness

The expression and turnover of Ag-specific peptide-MHC class II (pMHC-II) on the surface of dendritic cells (DCs) is essential for their ability to efficiently activate CD4 T cells. Ubiquitination of pMHC-II by the E3 ubiquitin ligase March-I regulates surface expression and survival of pMHC-II in DCs. We now show that despite their high levels of surface pMHC-II, MHC class II (MHC-II) ubiquitination-deficient mouse DCs are functionally defective; they are poor stimulators of naive CD4 T cells and secrete IL-12 in response to LPS stimulation poorly. MHC-II ubiquitination-mutant DC defects are cell intrinsic, and single-cell RNA sequencing demonstrates that these DCs have an altered gene expression signature as compared with wild-type DCs. Curiously, these functional and gene transcription defects are reversed by activating the DCs with LPS. These results show that dysregulation of MHC-II turnover suppresses DC development and function.