Ubiquitin regulates the trafficking of receptors to and from the cell surface with important consequences for immunity. Here, we have investigated ubiquitin-mediated trafficking of major histocompatibility complex II (MHC II), a molecule that is critical for CD4+ T cell responses. First, we investigated the ubiquitin machinery involved in MHC II trafficking in different primary cell types. Using mice lacking membrane associated RING-CH (MARCH) E3 ligases, we identified MARCH 1 as the major E3 ligase responsible for ubiquitination of MHC II in a diverse array of haemopoietic cell types. In contrast, in non haemopoietic cells, MHC II trafficking is controlled by closely related family member MARCH 8. In the thymic epithelium, MARCH 8 ubiquitination of MHC II, and MHC II surface trafficking, is regulated by CD83 with important consequences for CD4+ T cell development. Next, we have examined the ubiquitin code associated with MHC II trafficking in different primary immune cells. We detect distinct patterns of MHC II ubiquitination with the length of the ubiquitin chain and the ubiquitin code (chain linkages) varying for different cell types. This implicates different ubiquitination machinery for MHC II trafficking in specific cell types. Identification of novel components of the ubiquitination machinery involved is currently under investigation with CRISPR/cas-9 screening. In summary, we have undertaken in depth analysis of MHC II trafficking in primary immune and non haemopoietic cells. Our findings uncover cell-type specific ubiquitination events and highlight ubiquitination as an important post translational modification that regulates the trafficking of molecules for effective immunity.