Understanding the systemic roles of exosomes in innate immunity

Abstract

Cell-cell communication is critical for rapidly spreading the message of infection and enabling the innate immune system to mount a broad response against the pathogen. Exosomes are nanovesicles (~50nm in diameter) that are released extracellularly by all cell types. Their ability to transmit messages between cells at a distance and their rapid transport through the body makes them ideal messengers for establishing innate immune responses. However, their utilization of transport pathways in vivo was uncharacterized. The central role of lymphatic transport in trafficking exosomes in vivo was established for the first time in this thesis. Furthermore, differential distribution of exosomes in the draining lymph nodes that is dependent on the lymphatic flow has been established and macrophages and B-cells were identified as key players in exosome uptake. The distal recapitulation of the local toll-like receptor response via exosomes definitively established their ability to disseminate innate immune information in vitro. This is the first delineation of the kinetics of the response accompanied with abrogation of the action-at-a-distance signaling of exosomes by UV irradiation, demonstrating that RNA is crucial for their effector function. The impact of exosome uptake in whole lymph node and macrophages uptake is elucidated to show reprogramming of the node to a pro-inflammatory state and M1 macrophage polarization. Therefore, this work characterized the role of exosomes in initiating an innate immune response comprehensively in the context of a viral infection both in vitro and in vivo.