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

BACKGROUND: 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. METHODS: Ex vivo differentiation of naive CD4+ T cells was conducted to assess the effect of EVs on cytokine production and proliferation of Th1, Th2, Th17, and regulatory T (Treg) cells. These effects were further tested in vivo using the experimental autoimmune myocarditis (EAM) model. RESULTS: 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 (Treg) cells. Exposure of Treg cells to EVs results in faster proliferation, augmented production of IL10, and polarization toward an intermediate FOXP3+RORgt+ phenotype. In experimental autoimmune myocarditis, EVs attenuate cardiac inflammation and functional decline, in association with increased numbers of splenic IL10+-Treg cells. CONCLUSIONS: 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. J Heart Lung Transplant 2021;40:1387-1395 (c) 2021 International Society for Heart and Lung Transplantation. All rights reserved.

Automated summary

The study demonstrates that EVs secreted by heart stromal/progenitor cells can selectively influence the phenotype, activity, and proliferation of regulatory T cells, leading to mitigated cardiac inflammation and functional decline in experimental autoimmune myocarditis.