T regulatory cells-derived extracellular vesicles and their contribution to the generation of immune tolerance

Abstract

T regulatory (Treg) cells have a major role in the maintenance of immune tolerance against self and foreign antigens through the control of harmful inflammation. Treg cells exert immunosuppressive function by several mechanisms, which can be distinguished as contact dependent or independent. Recently, the secretion of extracellular vesicles (EVs) by Treg cells has been reported as a novel suppressive mechanism capable of modulating immunity in a cell‐contact independent and targeted manner, which has been identified in different pathologic scenarios. EVs are cell‐derived membranous structures involved in physiologic and pathologic processes through protein, lipid, and genetic material exchange, which allow intercellular communication. In this review, we revise and discuss current knowledge on Treg cells‐mediated immune tolerance giving special attention to the production and release of EVs. Multiple studies support that Treg cells‐derived EVs represent a refined intercellular exchange device with the capacity of modulating immune responses, thus creating a tolerogenic microenvironment in a cell‐free manner. The mechanisms proposed encompass miRNAs‐induced gene silencing, the action of surface proteins and the transmission of enzymes. These observations gain relevance by the fact that Treg cells are susceptible to converting into effector T cells after exposition to inflammatory environments. Yet, in contrast to their cells of origin, EVs are unlikely to be modified under inflammatory conditions, highlighting the advantage of their use. Moreover, we speculate in the possibility that Treg cells may contribute to infectious tolerance via vesicle secretion, intervening with CD4+ T cells differentiation and/or stability.

Regulatory T Cells: Regulation of Identity and Function

“…Treg cells may undergo transformation into effector T cells following exposure to inflammatory conditions lends credence to these findings. EVs, on the other hand, are unlikely to be changed under inflammatory circumstances, in contrast to their cells of origin (82).…”

“…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.…”

Nano-Microparticle Platforms in Developing Next-Generation Vaccines

“…Intriguingly, Tregs are able to release EVs with tolerogenic properties, which contributes to modulating the immune response without the need of direct cell-to-cell interaction. This activity could be either ascribed to the transfer of miRNAs or proteins to the target cells or attributed to the activity of surface proteins expressed on the vesicles [118]. Moreover, several studies performed in mice have shown that EVs derived from foxp3 + Tregs display suppressive functions mediated by molecules, such as CD73, which impair cytokine release from T cells by converting AMP into adenosine [119], or let-7d miRNA, which suppresses T H 1 proliferation and IFN-γ release by inhibiting cyclooxygenase-2 (Cox-2) [120].…”

Mechanisms of Action of EGFR Tyrosine Kinase Receptor Incorporated in Extracellular Vesicles

“…Copious evidence has documented that tumour-derived EVs contribute directly to the generation of suppressive immune cells, and this occurs through different mechanisms including transfer of genetic and protein material, and direct signalling [171][172][173]. In turn, suppressive immune cells can release their own EVs propagating immune suppressive effects at a cellular level [174].…”