Membrane vesicles as conveyors of immune responses

Abstract

Secreted membrane vesicles are heterogeneous spherical structures that are limited by a lipid bilayer and contain cytoplasmic components from the donor cell. Secreted vesicles can be classified according to their intracellular origin: microvesicles, ectosomes and viruses are shed from the plasma membrane, whereas exosomes and exosome-like vesicles form in intracellular multivesicular compartments and are secreted following fusion of these compartments with the plasma membrane. Membrane vesicles can be captured by neighbouring recipient cells through the interaction of vesicular ligands with cellular receptors (such as interactions between intracellular adhesion molecule 1 and lymphocyte function-associated antigen 1, phosphatidylserine and T cell immunoglobulin domain and mucin domain protein 4, as well as integrins and adhesion molecules). The precise mechanisms of interaction remain poorly characterized, but several studies suggest that vesicles can be internalized and might fuse with the recipient cell either at the plasma membrane or after internalization. Exosomes and microvesicles contain transmembrane proteins, soluble cytoplasmic components and lipids, but also mRNAs and microRNAs derived from the donor cell. Recent in vitro studies show that mRNAs can be transferred to and transcribed in recipient cells, suggesting that secreted vesicles could modify the genetic profile of recipient cells. Exosomes secreted by dendritic cells (DCs) bear functional preformed peptide–MHC complexes and can either directly activate antigen-specific effector T cells or transfer these complexes to recipient DCs to activate naive antigen-specific T cells. Material transferred by exosomes derived from all cell types (in particular tumours) can be processed and presented by recipient DCs. Exosomes and microvesicles secreted by tumours have been shown to inhibit immune responses in an antigen-independent manner, especially by switching monocyte and T cell differentiation towards a tolerogenic phenotype. However, when injected with adjuvants or purified from stressed tumour cells, exosomes can induce potent antitumour responses. Most studies described in this Review were carried out using vesicles purified in vitro from cultured cells or ex vivo from biological fluids. Membrane vesicles are secreted in vivo, but the demonstration of a function for this in vivo secretion will require the identification of tools to specifically inhibit their secretion. Exosomes derived from DCs or tumours from patients with cancer have been used for immunotherapies, but clinical responses are limited. Future clinical trials will benefit from recent preclinical studies on exosomes and should involve a combination of exosomes and other immunomodulatory approaches.