Bcl2-Like Protein 12 Is Required for the Aberrant T Helper-2 Polarization in the Heart by Enhancing Interleukin-4 Expression and Compromising Apoptotic Machinery in CD4+ T Cells

Abstract

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.

Soluble CD83 alleviates experimental allergic rhinitis through modulating antigen-specific Th2 cell property

“…The data show that sTh2 cells of subjects with allergic diseases show apoptosis resistance as well as high levels of Bcl2L12. Inhibition of Bcl2L12 can increase the sensitiveness of CD4 + T cells to apoptosis inducers [12]. The present data reveal another aspect of this phenomenon.…”

“…Bcl2L12 is an apoptosis inhibitor. Cells with high Bcl2L12 levels are resistant to apoptosis inducers [12]. The data show that sTh2 cells of subjects with allergic diseases show apoptosis resistance as well as high levels of Bcl2L12.…”

“…Our previous work indicates that the B cell lymphoma-2-like protein-12 (Bcl2L12), an apoptosis inhibitor, plays an important role in the development of Th2 polarization [12]. Inhibition of Bcl2L12 efficiently suppresses Th2 response-related immune inflammation [12]. Yet, the causative factors of Bcl2L12-over expression remain to be further investigated.…”

Dysregulated CD4+ T Cells and microRNAs in Myocarditis

“…Increased levels of Th2 cells and related cytokines were detected in the hearts of patients with myocarditis and advanced heart failure, compared to patients with DCM (12). Furthermore, an anti-allergic Th2 cytokine inhibitor ameliorated cardiac inflammation in a patient with acute eosinophilic myocarditis (59), underscoring the critical role of Th2 cells in myocarditis.…”

“…T helper (Th) 1 cells initiate tissue damage, promote early responses, and protect against excessive cardiac inflammation (8,10,11). Th 2 cells are critical in severe myocarditis with eosinophil expansion (12,13). Th17 cells are major regulators in chronic phase (8,14,15).…”