Expedition EVeresT: Exploring extracellular vesicles as regulators of T cell responses

Abstract

Extracellular vesicles (EVs), including exosomes and ectosomes, are highly heterogenous lipid bilayer- enclosed structures comprising of various surface proteins and cargo molecules such as nucleic acids, (enzymatic) proteins, and metabolites. EVs are key players in intercellular communication and due to their heterogeneity, they are proficient in modulating many processes including immune responses. Therefore, this review focuses on the current knowledge on the roles of EVs in orchestrating T cell activation and differentiation in health and disease. It highlights the fact that depending on their molecular cargos, EVs can cause multimodal impact on T cells through various mechanisms namely via DNA/RNA regulation, antigen presentation and modulation of co-stimulation, as well as metabolic reprogramming. To modulate T cell responses, EVs can either directly exert their effect on T cells or indirectly via intermediary cells such as antigen presenting cells and via manipulation of the microenvironment. The potential of EVs as T cell targeting therapeutic agents in the context of generating antitumor immunity as well as preventing chronic inflammatory and autoimmune diseases is also discussed. Further research including setting up human clinical trials and improving current methods of EV generation to comply with Current Good Manufacturing Practice regulations will push EVs one step closer to being used in clinical practice. Considering the current evidences, it is very likely that novel EV-based T cell modulating therapies will emerge in the coming years.