Division of Cardiology, Heart and Stroke/Richard Lewar Centre of Excellence, University Health Network, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario, Canada.
Circulation. 2010 Jun 22;121(24):2624-34. doi: 10.1161/CIRCULATIONAHA.109.893248. Epub 2010 Jun 7.
Coxsackievirus B3 infection is an excellent model of human myocarditis and dilated cardiomyopathy. Cardiac injury is caused either by a direct cytopathic effect of the virus or through immune-mediated mechanisms. Regulatory T cells (Tregs) play an important role in the negative modulation of host immune responses and set the threshold of autoimmune activation. This study was designed to test the protective effects of Tregs and to determine the underlying mechanisms.
Carboxyfluorescein diacetate succinimidyl ester-labeled Tregs or naïve CD4(+) T cells were injected intravenously once every 2 weeks 3 times into mice. The mice were then challenged with intraperitoneal coxsackievirus B3 immediately after the last cell transfer. Transfer of Tregs showed higher survival rates than transfer of CD4(+) T cells (P=0.0136) but not compared with the PBS injection group (P=0.0589). Interestingly, Tregs also significantly decreased virus titers and inflammatory scores in the heart. Transforming growth factor-beta and phosphorylated AKT were upregulated in Tregs-transferred mice and coxsackie-adenovirus receptor expression was decreased in the heart compared with control groups. Transforming growth factor-beta decreased coxsackie-adenovirus receptor expression and inhibited coxsackievirus B3 infection in HL-1 cells and neonatal cardiac myocytes. Splenocytes collected from Treg-, CD4(+) T-cell-, and PBS-treated mice proliferated equally when stimulated with heat-inactivated virus, whereas in the Treg group, the proliferation rate was reduced significantly when stimulated with noninfected heart tissue homogenate.
Adoptive transfer of Tregs protected mice from coxsackievirus B3-induced myocarditis through the transforming growth factor beta-coxsackie-adenovirus receptor pathway and thus suppresses the immune response to cardiac tissue, maintaining the antiviral immune response.
柯萨奇病毒 B3 感染是人类心肌炎和扩张型心肌病的极佳模型。心脏损伤是由病毒的直接细胞病变作用引起的，或是通过免疫介导的机制引起的。调节性 T 细胞（Tregs）在负性调节宿主免疫反应和设定自身免疫激活的阈值方面发挥着重要作用。本研究旨在测试 Tregs 的保护作用，并确定其潜在机制。
羧基荧光素二乙酸琥珀酰亚胺酯标记的 Tregs 或幼稚 CD4(+)T 细胞每隔 2 周静脉注射一次，共 3 次。在最后一次细胞转移后，立即用腹腔内柯萨奇病毒 B3 对小鼠进行攻击。与幼稚 CD4(+)T 细胞转导相比，Tregs 转导显示出更高的存活率（P=0.0136），但与 PBS 注射组相比没有差异（P=0.0589）。有趣的是，Tregs 还显著降低了心脏中的病毒滴度和炎症评分。与对照组相比，Tregs 转导小鼠的转化生长因子-β和磷酸化 AKT 上调，心脏中的柯萨奇病毒-腺病毒受体表达降低。转化生长因子-β降低了柯萨奇病毒-腺病毒受体的表达，并抑制了 HL-1 细胞和新生心肌细胞中的柯萨奇病毒 B3 感染。用热灭活病毒刺激从 Treg、CD4(+)T 细胞和 PBS 处理的小鼠中收集的脾细胞时，增殖率相等，而在 Treg 组中，当用未感染的心脏组织匀浆刺激时，增殖率显著降低。
通过转化生长因子-β-柯萨奇病毒-腺病毒受体途径，过继转移 Tregs 可保护小鼠免受柯萨奇病毒 B3 诱导的心肌炎，从而抑制对心脏组织的免疫反应，维持抗病毒免疫反应。
