REVIEWS
Regulation of immune responses by extracellular vesicles Paul D. Robbins1 and Adrian E. Morelli2
Abstract | Extracellular vesicles, including exosomes, are small membrane vesicles derived from multivesicular bodies or from the plasma membrane. Most, if not all, cell types release extracellular vesicles, which then enter the bodily fluids. These vesicles contain a subset of proteins, lipids and nucleic acids that are derived from the parent cell. It is thought that extracellular vesicles have important roles in intercellular communication, both locally and systemically, as they transfer their contents, including proteins, lipids and RNAs, between cells. Extracellular vesicles are involved in numerous physiological processes, and vesicles from both non-immune and immune cells have important roles in immune regulation. Moreover, extracellular vesicle‑based therapeutics are being developed and clinically tested for the treatment of inflammatory diseases, autoimmune disorders and cancer. Given the tremendous therapeutic potential of extracellular vesicles, this Review focuses on their role in modulating immune responses, as well as their potential therapeutic applications. microRNAs (miRNAs). Small non-coding RNAs (~22 nucleotides in length) that posttranscriptionally regulate gene expression by binding to seed sequences on target mRNAs, which results in mRNA degradation or inhibition of mRNA translation.
Department of Metabolism and Aging, The Scripps Research Institute, 130 Scripps Way #3B3, Jupiter, Florida 33458, USA. 2 Departments of Surgery and Immunology and T.E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. e‑mails: [email protected]; [email protected] doi:10.1038/nri3622 1
Almost all cells release different types of membrane microvesicle and nanovesicle, which have a variety of important physiological effects. Microvesicles mainly differ from nanovesicles in terms of their size and their mechanism of generation1–4. Microvesicles are released from the plasma membrane by shedding or budding, they are usually larger than 0.2 μm in size and have been referred to as microparticles or ectosomes. By contrast, nanovesicles, including exosomes, are between 30–100 nm in diameter, are characterized by an endocytic origin and are formed by the reverse budding of the peripheral membrane of multivesicular bodies (MVBs) or late endosomes (BOX 1). However, certain nanovesicles seem to be derived from the plasma membrane5. The protein content of different types of extracellular vesicle mostly reflects that of the parent cells and vesicles are enriched in certain molecules, including adhesion molecules, membrane trafficking molecules, cytoskeleton molecules, heat shock proteins, cytoplasmic enzymes, signal transduction proteins, cytokines, chemokines, proteinases and cell-specific antigens. Moreover, extracellular vesicles contain mRNAs, noncoding RNAs (ncRNAs), including microRNAs (miRNAs), and even extra-chromosomal DNA, such as amplified MYC6. Almost all cell types release extracellular vesicles that are found in the plasma and other bodily fluids, including breast milk, semen, saliva, urine and
sputum. Extracellular vesicles participate in important biological functions, acting as a mode of communication between cells. This intercellular communication can be conferred by mediators that are expressed on the surface of the extracellular vesicles or that are contained within the extracellular vesicle lumen. Extracellular vesicles that are produced by both immune and non-immune cells have important roles in the regulation of immunity. They can mediate immune stimulation or suppression and they can drive inflammatory, autoimmune and infectious disease pathology. Thus, extracellular vesicles have the potential to be used as therapeutic agents to modulate the immune system. In this Review, we focus on the biology of the 30–100 nm extracellular vesicles known as exosomes and the mechanisms through which they regulate the immune response. Moreover, we discuss the potential application of these extracellular vesicles in the treatment of inflammatory and autoimmune diseases as well as cancer.
Biogenesis and trafficking of exosomes Exosomes are generated by the inward budding of an endosomal membrane. The resulting invaginations are pinched off and released as intraluminal vesicles (ILVs) inside the endosomes, which are then termed MVBs1,3 (FIG. 1). MVBs can then follow either the secretory pathway or the lysosomal pathway. In the secretory pathway,
NATURE REVIEWS | IMMUNOLOGY
VOLUME 14 | MARCH 2014 | 195 © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Box 1 | General features of exosomes • Exosomes are extracellular vesicles (
Regulation of immune responses by extracellular vesicles Paul D. Robbins1 and Adrian E. Morelli2
Abstract | Extracellular vesicles, including exosomes, are small membrane vesicles derived from multivesicular bodies or from the plasma membrane. Most, if not all, cell types release extracellular vesicles, which then enter the bodily fluids. These vesicles contain a subset of proteins, lipids and nucleic acids that are derived from the parent cell. It is thought that extracellular vesicles have important roles in intercellular communication, both locally and systemically, as they transfer their contents, including proteins, lipids and RNAs, between cells. Extracellular vesicles are involved in numerous physiological processes, and vesicles from both non-immune and immune cells have important roles in immune regulation. Moreover, extracellular vesicle‑based therapeutics are being developed and clinically tested for the treatment of inflammatory diseases, autoimmune disorders and cancer. Given the tremendous therapeutic potential of extracellular vesicles, this Review focuses on their role in modulating immune responses, as well as their potential therapeutic applications. microRNAs (miRNAs). Small non-coding RNAs (~22 nucleotides in length) that posttranscriptionally regulate gene expression by binding to seed sequences on target mRNAs, which results in mRNA degradation or inhibition of mRNA translation.
Department of Metabolism and Aging, The Scripps Research Institute, 130 Scripps Way #3B3, Jupiter, Florida 33458, USA. 2 Departments of Surgery and Immunology and T.E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. e‑mails: [email protected]; [email protected] doi:10.1038/nri3622 1
Almost all cells release different types of membrane microvesicle and nanovesicle, which have a variety of important physiological effects. Microvesicles mainly differ from nanovesicles in terms of their size and their mechanism of generation1–4. Microvesicles are released from the plasma membrane by shedding or budding, they are usually larger than 0.2 μm in size and have been referred to as microparticles or ectosomes. By contrast, nanovesicles, including exosomes, are between 30–100 nm in diameter, are characterized by an endocytic origin and are formed by the reverse budding of the peripheral membrane of multivesicular bodies (MVBs) or late endosomes (BOX 1). However, certain nanovesicles seem to be derived from the plasma membrane5. The protein content of different types of extracellular vesicle mostly reflects that of the parent cells and vesicles are enriched in certain molecules, including adhesion molecules, membrane trafficking molecules, cytoskeleton molecules, heat shock proteins, cytoplasmic enzymes, signal transduction proteins, cytokines, chemokines, proteinases and cell-specific antigens. Moreover, extracellular vesicles contain mRNAs, noncoding RNAs (ncRNAs), including microRNAs (miRNAs), and even extra-chromosomal DNA, such as amplified MYC6. Almost all cell types release extracellular vesicles that are found in the plasma and other bodily fluids, including breast milk, semen, saliva, urine and
sputum. Extracellular vesicles participate in important biological functions, acting as a mode of communication between cells. This intercellular communication can be conferred by mediators that are expressed on the surface of the extracellular vesicles or that are contained within the extracellular vesicle lumen. Extracellular vesicles that are produced by both immune and non-immune cells have important roles in the regulation of immunity. They can mediate immune stimulation or suppression and they can drive inflammatory, autoimmune and infectious disease pathology. Thus, extracellular vesicles have the potential to be used as therapeutic agents to modulate the immune system. In this Review, we focus on the biology of the 30–100 nm extracellular vesicles known as exosomes and the mechanisms through which they regulate the immune response. Moreover, we discuss the potential application of these extracellular vesicles in the treatment of inflammatory and autoimmune diseases as well as cancer.
Biogenesis and trafficking of exosomes Exosomes are generated by the inward budding of an endosomal membrane. The resulting invaginations are pinched off and released as intraluminal vesicles (ILVs) inside the endosomes, which are then termed MVBs1,3 (FIG. 1). MVBs can then follow either the secretory pathway or the lysosomal pathway. In the secretory pathway,
NATURE REVIEWS | IMMUNOLOGY
VOLUME 14 | MARCH 2014 | 195 © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Box 1 | General features of exosomes • Exosomes are extracellular vesicles (
