The mechanism of immune tolerance is to be further understood. The present study aims to investigate the role of the Cardiac endothelial cell (CEC)-derived exosomes in the induction of regulatory B cells. In this study, CECs were isolated from the mouse heart. Exosomes were purified from the culture supernatant of the primary endothelial cells. The suppressor functions of the regulatory B cells were determined by flow cytometry. The results showed that the CEC-derived exosomes carried integrin αvβ6. Exposure to lipopolysaccharide (LPS) induced B cells to express the latent transforming growth factor (TGF)-β, the latter was converted to the active form, TGF-β, by the exosome-derived αvβ6. The B cells released TGF-β in response to re-exposure to the exosomes in the culture, which suppressed the effector T cell proliferation. We conclude that CEC-derived exosomes have the capacity to induce B cells with immune suppressor functions.
To inhibit the immune inflammation in the allografts can be beneficial to organ transplantation. This study aims to induce the donor antigen specific regulatory T cells (Treg cell) inhibit the immune inflammation in the allograft heart. In this study, peripheral exosomes were purified from the mouse serum. A heart transplantation mouse model was developed. The immune inflammation of the allograft heart was assessed by histology and flow cytometry. The results showed that the donor antigen-specific T helper (Th)2 pattern inflammation was observed in the allograft hearts; the inflammation was inhibited by immunizing the recipient mice with the donor-derived exosomes. Purified peripheral exosomes contained integrin MMP1a; the latter induced CD4+ T cells to express Fork head protein-3 and transforming growth factor (TGF)-β via inhibiting the Th2 transcription factor, GATA binding protein 3, in CD4+ T cells. Administration with the donor-derived exosomes significantly prolonged the allograft heart survival. We conclude that the donor-derived peripheral exosomes have the capacity to inhibit the immune inflammation in the allograft heart via inducing specific Treg cells, implicating that administration with the donor-derived exosomes may be beneficial to cardiac transplantation.
Background:
The biased T helper-2 (Th2) response plays a critical role in myocarditis. Bcl2-like protein 12 (Bcl2L12) is associated with the Th2 pattern of inflammation. This study aims to elucidate the role of Bcl2L12 in the pathogenesis of Th2-biased inflammation in the heart.
Methods:
Mice were treated with the myosin heavy-chain-α peptides to induce inflammation in the heart. Human hearts were collected from the surgically removed hearts of patients who had undergone heart transplantation.
Results:
The expression of Bcl2L12 was detected in CD4
+
T cells of the hearts, which was markedly higher in the hearts with myocarditis at the advanced stage of heart failure compared with the control (dilated cardiomyopathy) hearts without myocarditis. Mice with Bcl2L12-deficient CD4
+
T cells failed to induce the Th2-biased inflammation in the heart. CD4
+
T cells with a higher expression of Bcl2L12 were prone to differentiate into Th2 cells. Bcl2L12 formed a complex with GATA3 in CD4
+
T cells to enhance the binding between GATA3 and the
Il4
promoter, which promoted the
Il4
gene transcription. Bcl2L12 compromised the apoptotic machinery by inhibiting the expression of p53 in CD4
+
T cells to reduce the activation-induced CD4
+
T cell death.
Conclusions:
CD4
+
T cells isolated from hearts with myocarditis at the end stage of heart failure express high levels of Bcl2L12, and the latter is required for the development of aberrant Th2 polarization in the heart. The Bcl2L12 may be a novel target in the treatment of myocarditis as well as other Th2-biased inflammation.
Scientific Reports 6: Article number: 20077; published online: 29 January 2016; updated: 30 June 2017. The original HTML version of this Article listed an incorrect volume number. This has now been corrected in the HTML version; the PDF version was correct at the time of publication.
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