Regulation of chronic inflammatory and immune processes by extracellular vesicles

Abstract

Almost all cell types release extracellular vesicles (EVs), which are derived either from multivesicular bodies or from the plasma membrane. EVs contain a subset of proteins, lipids, and nucleic acids from the cell from which they are derived. EV factors, particularly small RNAs such as miRNAs, likely play important roles in cell-to-cell communication both locally and systemically. Most of the functions associated with EVs are in the regulation of immune responses to pathogens and cancer, as well as in regulating autoimmunity. This Review will focus on the different modes of immune regulation, both direct and indirect, by EVs. The therapeutic utility of EVs for the regulation of immune responses will also be discussed.

Figures

Figure 1. Regulation of immune responses by professional APCs.

Professional APCs, such as DCs, present MHC class I and II complexes with peptides (p-MHC) that are derived from captured exosomes. (A) EVs retained on the APC surface present their p-MHC complexes directly to T cells, where costimulatory molecules and other regulatory molecules can be provided by the APC (cross-dressing). The EVs also can be internalized, allowing them to transfer their peptides to MHC molecules of the host APCs. Endogenous antigens can be processed in a similar manner, and the resulting epitopes are loaded onto MHC class II molecules. Host MHC class II complexed with EV-derived peptides (p-MHC II) are transported to the cell surface for presentation to T cells. (B) Alternatively, EV interaction with and uptake by APCs can lead to increased production of cytokines, such as TGF-β1, and release of APC-derived EVs carrying p-MHC II that are able to regulate antigen-specific immune responses. For simplicity, only MHC class II complexes are shown, but similar events can occur for presentation of EV-derived peptides on MHC class I for presentation to CD8+ T cells.

Figure 2. Role of endogenous EVs in regulating immune responses.

(A) Resident APCs, such as macrophages in the tumor environment, can acquire tumor antigens either by uptake of tumor EVs or by phagocytosis of necrotic tumor cells. APCs then release MHC class II+ EVs into the circulation that are able to interact with immune cells at distant sites to suppress tumor antigen-specific immune responses; these are termed tolerogenic EVs. (B) Infection with a pathogen or immunization to an antigen results in acquisition of antigen by local APCs, followed by release of APC-derived EVs into the circulation. APC-derived EVs can carry the antigen and/or present antigen-derived epitopes in MHC class I and MHC class II complexes. Circulating EVs are taken up by APCs in the spleen or lymph nodes where they can modulate immune response to the antigen. It is hypothesized that these vesicles act to suppress the systemic immune response to the antigen or infection to limit the extent of inflammation or autoimmunity.

Figure 3. Modifying EVs for therapeutic applications.

APCs can be engineered in culture to generate immunoregulatory EVs for therapeutic applications. Antigen-specific effects can be achieved by pulsing the APCs with tumor- or pathogen-derived antigens or by transfer of antigen-encoding genes. Similarly, APCs can be modified to express immunosuppressive or immunostimulatory cytokines or ligands, which can render the APC-derived EVs able to suppress or stimulate antigen-specific immune responses. The expression of costimulatory ligands in the APC can result in EVs with increased levels of the ligands, thereby directly affecting the immunoregulatory activity of the EVs. Finally, the EVs themselves can be modified to carry immunomodulatory small RNAs, such as miRNAs or antagomIRs. CTL, cytotoxic T lymphocyte.