A cytoplasmic tail motif directs HLA-E to clathrin-mediated endocytosis and valosin-containing-protein-mediated recycling

Recent discoveries highlight the effectiveness of major histocompatibility complex (MHC)-E-restricted CD8+ T cell responses in controlling certain infections, particularly in a rhesus cytomegalovirus (RhCMV68-1)-vectored simian immunodeficiency virus (SIV) vaccine. In this context, these responses are preferentially elicited and are crucial for enabling vaccinated rhesus macaques to eradicate an SIV challenge. To harness human leukocyte antigen (HLA)-E-restricted CD8+ T cell responses for therapeutic purposes, it is essential to understand how these responses are primed, especially the mechanisms regulating MHC-E trafficking within endosomal pathways. Here, we identified a novel lysine/tryptophan-based motif in the HLA-E cytoplasmic tail that promotes rapid surface turnover via clathrin-mediated endocytosis. This motif, combined with strong binding peptides, also facilitates HLA-E recycling through a distinct valosin-containing protein-dependent pathway. Additionally, we show that this motif and its associated endosomal transport mechanisms are conserved in rhesus macaques and Mauritian-origin cynomolgus macaques. These findings advance our understanding of how MHC-E regulates immune functions through unconventional transport processes and offer insights for stimulating HLA-E-restricted CD8+ T cell responses in immunotherapy development.