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

Abstract

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.

Keywords: Antigen-presenting cells; Cross-dressing; Dendritic cells; Exosomes; Extracellular vesicles; MHC.

Fig. 1

Mechanisms of presentation of pMHCs by APCs to cognate T cells include direct presentation, cross-presentation, and presentation via MHC cross-dressed APCs. A) Through direct presentation, APCs present endogenous MHC-II molecules loaded with peptides resulting from processing of internalized Ags to CD4 T cells; or endogenous MHC-I molecules loaded with peptides derived from endogenous proteins synthesized by the APCs or from proteins of microbes that replicate in the cytosol (i.e. from virally-infected cells, tumor cells) to CD8 T cells. B) APCs cross-present to CD8 T cells endogenous MHC-I molecules loaded with peptides resulting from processing of internalized Ags. C) APCs cross-dressed with exogenous EVs carrying pMHCs on the vesicle surface present the pre-formed pMHC-I and pMHC-II to CD8 T cells and CD4 T cells, respectively, without further Ag-processing of the acquired pMHCs by the APCs.

Fig. 2

Donor MHC cross-dressing of recipient APCs in transplantation. After transplantation of skin or heart allografts in mice, recipient APCs (mainly cDCs) resident in graft-draining SLOs become cross-dressed with donor intact MHC molecules, which are acquired via capture of clusters of donor-derived EVs with characteristic of exosomes that carry donor intact MHC molecules on the vesicle surface. The donor-derived EVs are released directly by cells from the grafts or by the relatively few donor migrating DCs that reach the graft-draining SLOs. The 3-cell model predicts that individual recipient cDCs cross-dressed with donor-derived EVs present: (i) host MHC-II molecules loaded with donor allo-peptides to CD4 T cells, through the indirect pathway (i.e. canonical pathway of Ag-presentation); and (ii) donor intact MHC molecules on the surface of the attached EVs to directly alloreactive CD8 T cells, via the semi-direct pathway. The indirect pathway CD4 T cells promotes maturation of the MHC cross-dressed recipient cDCs, which then stimulate the direct pathway CD8 T cells.

Fig. 3

Pathways of MHC-I cross-dressing of APCs during viral infections. For viruses that do not infect or infect poorly APCs, virus-derived pMHC-I can be transferred from peripheral tissue parenchymal or stromal cells to tissue-resident cDCs before cDC migration to SLOs, where the pMHC-I cross-dressed migrating cDCs prime anti-viral cytotoxic CD8 T cells. Alternatively, tissue-resident cDCs that become infected with virus in periphery mobilize to SLOs and transfer virus-derived pMHC-I to SLO-resident cDCs, which initiate the anti-viral CD8 T cell response. Alternatively, virus-derived pMHC-I could be transferred via a cell-free mechanism, likely mediated through EVs, to SLO-resident APCs.

Fig. 4

Acquisition by APCs of MHC molecules loaded with tumor-associated Ag (TAA)-derived peptides released from tumor cells or cell-based anti-tumor vaccines. A) Tumor cells transfer MHC-I molecules loaded with TAA-derived peptides, likely via EVs, to DCs of myeloid lineage and to plasmacytoid DCs, a phenomenon that overcomes the limited capability of plasmacytoid DCs for cross-presentation to CD8 T cells. B) MHC-II⁺ tumor cell- and DC-based vaccines injected s.c. prime anti-tumor T cells through SLO-resident cDCs cross-dressed with MHC molecules loaded with TAA-derived peptides released, possibly through EVs, by the injected cells.