Regulatory T cell activation, proliferation, and reprogramming induced by extracellular vesicles

Extracellular vesicles (EVs) from heart stromal/progenitor cells modulate innate immunity, with salutary effects in a variety of cardiac disease models. Little is known, however, about the effects of these EVs on adaptive immunity.

Ex vivo differentiation of naïve CD4⁺ T cells was conducted to assess the effect of EVs on cytokine production and proliferation of Th1, Th2, Th17, and regulatory T (T_reg) cells. These effects were further tested in vivo using the experimental autoimmune myocarditis (EAM) model.

Using differentiated CD4⁺ T cells, we show that EVs secreted by human-derived heart stromal/progenitor cells selectively influence the phenotype, activity, and proliferation of regulatory T (T_reg) cells. Exposure of T_reg cells to EVs results in faster proliferation, augmented production of IL-10, and polarization toward an intermediate FOXP3⁺RORγt⁺ phenotype. In experimental autoimmune myocarditis, EVs attenuate cardiac inflammation and functional decline, in association with increased numbers of splenic IL10⁺-T_reg cells.

T cell modulation by EVs represents a novel therapeutic approach to inflammation, harnessing endogenous immunosuppressive mechanisms that may be applied in solid organ transplantation, graft-versus-host disease, and autoimmune disorders.