Regulation of immune responses by extracellular vesicles

Key Points Extracellular vesicles, including exosomes, are small membrane vesicles that are derived from multivesicular bodies or that bud from the plasma membrane. Most, if not all, cell types release extracellular vesicles that then enter almost all bodily fluids. Extracellular vesicles, which carry proteins, lipids, mRNAs and non-coding RNAs including microRNAs, have important roles in intercellular communication, both locally and systemically, by transferring their contents between cells. Extracellular vesicles are involved in numerous physiological processes, and vesicles from both non-immune cells, such as stem cells, and immune cells participate in immune regulation. As a result of the immunoregulatory activity of extracellular vesicles, therapeutic approaches using these vesicles are being developed and clinically tested for the treatment of inflammatory and autoimmune diseases and cancer. Extracellular vesicles that carry tumour or pathogenic peptides presented by MHC class I and MHC class II complexes can stimulate CD4 + and CD8 + T cells directly as well as indirectly through an interaction with antigen-presenting cells (APCs). Peptide–MHC complexes of extracellular vesicles that become attached or fused to APC surfaces might also be directly presented to T cells without the need for peptide–MHC complex reprocessing through a mechanism known as cross-dressing. Extracellular vesicles can be immunostimulatory through the transfer of both antigens and signals to APCs to promote their activation into immunogenic APCs. By contrast, certain extracellular vesicles can render APCs immunosuppressive through multiple mechanisms, which results in the induction of regulatory T cells. The immunoregulatory activity of tumour-derived and APC-derived extracellular vesicles can be enhanced by treatment of the parental cells with cytokines, by stress (such as heat shock) or by gene transfer of immunoregulatory factors such as CD95 ligand, indoleamine 2,3-dioxygenase or interleukin-4. Extracellular vesicles, including exosomes, provide a means of intercellular communication for immune regulation. Here, the authors describe how the proteins, nucleic acids and other molecules that they carry influence immune responses, and explore their potential use in the treatment of inflammatory and autoimmune diseases, and cancer. Extracellular vesicles, including exosomes, are small membrane vesicles derived from multivesicular bodies or from the plasma membrane. Most, if not