Extracellular vesicle signaling in regulatory T cell biology: From immune suppression to microenvironmental crosstalk.

Regulatory T cells (Tregs) are essential for maintaining immune homeostasis, yet classical suppressive mechanisms alone do not fully explain how tolerance is propagated across tissues and sustained over time. Extracellular vesicles (EVs), particularly exosome-enriched small EVs, have emerged as an important additional layer of Treg-associated communication by enabling the selective transfer of proteins, lipids and regulatory RNAs between cells. In this review, we examine the reciprocal EV-Treg axis, highlighting how Treg-derived EVs extend suppressive function beyond direct cell contact by modulating dendritic cells, restraining effector T-cell responses, promoting regulatory macrophage polarization and supporting tissue repair. We further discuss how EVs released by immune, epithelial, stromal, microbial and tumor-associated cells shape Treg differentiation, stability and functional specialization in diverse physiological and pathological settings. Across autoimmunity, transplantation, barrier inflammation, infection and cancer, this bidirectional crosstalk emerges as a context-dependent regulator of immune tolerance that may either preserve tissue homeostasis or promote pathological immune suppression. We finally consider the therapeutic potential of targeting or engineering EV-Treg interactions as a cell-free strategy for precision immunomodulation.