Immune modulation by complement receptor 3-dependent human monocyte TGF-β1-transporting vesicles

Extracellular vesicles have an important function in cellular communication. Here, we show that human and mouse monocytes release TGF-beta 1-transporting vesicles in response to the pathogenic fungus Candida albicans. Soluble beta -glucan from C. albicans binds to complement receptor 3 (CR3, also known as CD11b/CD18) on monocytes and induces the release of TGF-beta 1-transporting vesicles. CR3-dependence is demonstrated using CR3-deficient (CD11b knockout) monocytes generated by CRISPR-CAS9 genome editing and isolated from CR3-deficient (CD11b knockout) mice. These vesicles reduce the pro-inflammatory response in human M1-macrophages as well as in whole blood. Binding of the vesicle-transported TGF-beta 1 to the TGF-beta receptor inhibits IL1B transcription via the SMAD7 pathway in whole blood and induces TGFB1 transcription in endothelial cells, which is resolved upon TGF-beta 1 inhibition. Notably, human complement-opsonized apoptotic bodies induce production of similar TGF-beta 1-transporting vesicles in monocytes, suggesting that the early immune response might be suppressed through this CR3-dependent anti-inflammatory vesicle pathway. Extracellular vesicles can carry immunoregulatory cytokines such as TGF-beta. Here the authors use CD11b-deficient mice and macrophages to show that such vesicles carrying TGF-beta are produced in response to Candida albicans infections and can limit the proinflammatory response partly via a positive feedback on TGF-beta production by endothelial cells.