Extracellular vesicle-mediated MHC cross-dressing in immune homeostasis, transplantation, infectious diseases, and cancer

Furong Zeng, Adrian E. Morelli

Eukaryotic cells employ different types of extracellular vesicles (EVs) to exchange proteins, mRNAs, non-coding regulatory RNAs, carbohydrates, and lipids. Cells of the immune system, in particular antigen (Ag)-presenting cells (APCs), acquire major histocompatibility complex (MHC) class I and II molecules loaded with antigenic peptides from leukocytes and tissue parenchymal and stromal cells, through a mechanism known as MHC cross-dressing. Increasing evidence indicates that cross-dressing of APCs with pre-formed Ag-peptide/MHC complexes (pMHCs) is mediated via passage of clusters of EVs with characteristics of exosomes. A percentage of the transferred EVs remain attached to the acceptor APCs, with the appropriate orientation, at sufficient concentration within localized areas of the plasma membrane, and for sufficient time, so the preformed pMHCs carried by the EVs are presented without further processing, to cognate T cells. Although its biological relevance is not fully understood, numerous studies have demonstrated that MHC cross-dressing of APCs represents a pathway of Ag presentation of acquired pre-formed pMHCs to T cells-alternative to direct and cross-presentation-participate in immune homeostasis and T cell tolerance, cross-regulate alloreactive T cells with different MHC restricted specificities, and is a mechanism of Ag spreading for autologous, allogeneic, microbial, tumor, or vaccine-delivered Ags. Here, we compare MHC cross-dressing with other mechanisms and terminologies used for pMHC transfer, including trogocytosis. We discuss the experimental evidence, mostly from in vitro and ex vivo studies, of the role of MHC cross-dressing of APCs via EVs in positive or negative regulation of T cell immunity in the steady state, transplantation, microbial diseases, and cancer.