Abstract
Th17 cells play a key role in the progression of coxsackievirus B3 (CVB3)-induced acute viral myocarditis (AVMC). However, the direct effect of virus on Th17 cell differentiation is still unknown. Recently, nucleoporin (Nup) 98 has been proved to be associated with lymphocyte differentiation. Therefore, we investigated whether Nup98 mediated Th17 cell differentiation in AVMC. In our study, patients with AVMC and healthy controls were recruited. The results showed that CVB3 could enter into the CD4+ T cells in AVMC patients and healthy controls. After transfecting purified CD4+ T cells with CVB3 in vitro, the Th17 cell frequency, IL-17 secretion, and RORγT synthesis were increased while the Nup98 levels were decreased. Furthermore, down-regulating Nup98 expression by siRNA-Nup98 in CD4+ T cells resulted in the elevated Th17 cell frequency and IL-17 secretion, along with enhanced levels of RORγT, dissociative p300/CBP, and acetylated Stat3. Up-regulation of Nup98 expression by pcDNA3.1-Nup98 showed the opposite effects. Our results suggested that CVB3 directly induced CD4+ T cell differentiation into Th17 cells by inhibiting Nup98 expression, representing a therapeutic target in AVMC.
Highlights
Acute viral myocarditis (AVMC) is triggered by viral infection and is characterized by myocardial inflammation, which progresses to chronic dilated cardiomyopathy (DCM) and heart failure (Dennert et al, 2008)
The data showed that the coxsackievirus B3 (CVB3) titer in CD4+ T cells treated with anti-Decay-accelerating factor (DAF) mAb was significantly lower (P = 0.043) than those treated with saline and isotype controls (Figures 4C,D). These data suggested that the entry of CVB3 into human CD4+ T cells might be mediated by DAF receptors rather than coxsackie-adenovirus receptor (CAR)
We found that CVB3 was present in CD4+ T cells of acute viral myocarditis (AVMC) patients
Summary
Acute viral myocarditis (AVMC) is triggered by viral infection and is characterized by myocardial inflammation, which progresses to chronic dilated cardiomyopathy (DCM) and heart failure (Dennert et al, 2008). CD4+ Th17 cells promote the development of AVMC by facilitating viral replication, inflammation and autoantibody production (Yuan et al, 2010a,b). Previous studies revealed that viral infection induced the activation of innate immune cells such as macrophages and dendritic cells (DCs), which indirectly contribute to Th17 cell differentiation by secreting inflammatory cytokines and generating co-stimulatary signals (Fairweather et al, 2005; Huang and Yang, 2009; Yajima and Knowlton, 2009; Rose, 2011). The direct effect of virus on Th17 cell differentiation is still unknown
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