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 naïve 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 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+-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.
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 naïve 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 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+-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.
Authors: Caspar Ohnmacht; Joo-Hong Park; Sascha Cording; James B Wing; Koji Atarashi; Yuuki Obata; Valérie Gaboriau-Routhiau; Rute Marques; Sophie Dulauroy; Maria Fedoseeva; Meinrad Busslinger; Nadine Cerf-Bensussan; Ivo G Boneca; David Voehringer; Koji Hase; Kenya Honda; Shimon Sakaguchi; Gérard Eberl Journal: Science Date: 2015-07-09 Impact factor: 47.728
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Authors: Ahmed G E Ibrahim; Chang Li; Russel Rogers; Mario Fournier; Liang Li; Sharon D Vaturi; Travis Antes; Lizbeth Sanchez; Akbarshakh Akhmerov; Jennifer Johnson Moseley; Brooke Tobin; Luis Rodriguez-Borlado; Rachel R Smith; Linda Marbán; Eduardo Marbán Journal: Nat Biomed Eng Date: 2019-08-26 Impact factor: 25.671
Authors: Raj R Makkar; Dean J Kereiakes; Frank Aguirre; Glenn Kowalchuk; Tarun Chakravarty; Konstantinos Malliaras; Gary S Francis; Thomas J Povsic; Richard Schatz; Jay H Traverse; Janice M Pogoda; Rachel R Smith; Linda Marbán; Deborah D Ascheim; Mohammad R Ostovaneh; João A C Lima; Anthony DeMaria; Eduardo Marbán; Timothy D Henry Journal: Eur Heart J Date: 2020-09-21 Impact factor: 29.983