Regulatory T Cell Extracellular Vesicles Modify T-Effector Cell Cytokine Production and Protect Against Human Skin Allograft Damage

Abstract

Regulatory T cells (Tregs) are a subpopulation of CD4 + T cells with a fundamental role in maintaining immune homeostasis and inhibiting unwanted immune responses using several different mechanisms. Recently, the intercellular transfer of molecules between Tregs and their target cells has been shown via trogocytosis and the release of small extracellular vesicles (sEVs). In this study, CD4 + CD25 + CD127 lo human Tregs were found to produce sEVs capable of inhibiting the proliferation of effector T cells (Teffs) in a dose dependent manner. These vesicles also modified the cytokine profile of Teffs leading to an increase in the production of IL-4 and IL-10 whilst simultaneously decreasing the levels of IL-6, IL-2, and IFNγ. MicroRNAs found enriched in the Treg EVs were indirectly linked to the changes in the cytokine profile observed. In a humanized mouse skin transplant model, human Treg derived EVs inhibited alloimmune-mediated skin tissue damage by limiting immune cell infiltration. Taken together, Treg sEVs may represent an exciting cell-free therapy to promote transplant survival.

Regulatory T Cells: Regulation of Identity and Function

“…Following TCR activation, CD4+CD25+ Tregs have been shown to release EVs in rodents and human settings. These vesicles exhibit immunological modulatory abilities in vitro, comparable to the cell from which they were originated (81)(82)(83). Murine Treg EVs have been shown to reduce CD4+ Teff cell proliferation, as well as IL-2 and IFNg release, and enhance IL-10 production by murine DCs in recent studies.…”

Stem Cells-Derived Extracellular Vesicles: Potential Therapeutics for Wound Healing in Chronic Inflammatory Skin Diseases

“…EVs/Exs activate the immune response, yet, depending on their cellular origin, they can also act as key immunoregulators/suppressers. Human regulatory T cell-secreted EVs/Exs suppress effector T cell proliferation and cytokine production in vitro, and can prevent allograft rejection in vivo [ 33 ]. Tumor-derived EVs/Exs express FasL and TRAIL membranous death ligands as well as regulatory proteins such as PD-L1 and CD40L [ 34 , 35 ].…”

Extracellular Vesicles in Oncology: from Immune Suppression to Immunotherapy

“…TMEs are enriched in Tregs that create an immunosuppressive environment to promote oncogenic properties. Treg-derived exosomes have also been shown to maintain immune tolerance ( 96 ). Interaction of DCs with exosomes produced by Tregs and transfer of miRNA-150-5p and miR-142-3p from the Treg exosomes to DCs suppresses DCs functions and leads to an immunosuppressive TME ( 97 ).…”