Sesti-Costa Renata, Françozo Marcela Cristina Santiago, Silva Grace Kelly, Proenca-Modena José Luiz, Silva João Santana
Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research GmbH, Hannover, Germany.
PLoS One. 2017 Oct 3;12(10):e0185819. doi: 10.1371/journal.pone.0185819. eCollection 2017.
Type B coxsackievirus (CVB) is a common cause of acute and chronic myocarditis, meningitis and pancreatitis, often leading to heart failure and pancreatic deficiency. The polarization of CD4+ T lymphocytes and their cytokine milieu are key factors in the outcome of CVB-induced diseases. Thus, sensing the virus and driving the adaptive immune response are essential for the establishment of a protective immune response. TLR3 is a crucial virus recognition receptor that confers the host with resistance to CVB infection. In the current study, we found that TLR3 expression in dendritic cells plays a role in their activation upon CVB3 infection in vitro, as TLR3-deficient dendritic cells up-regulate CD80 and CD86 to a less degree than WT cells. Instead, they up-regulated the inhibitory molecule PD-L1 and secreted considerably lower levels of TNF-α and IL-10 and a higher level of IL-23. T lymphocyte proliferation in co-culture with CVB3-infected dendritic cells was increased by TLR3-expressing DCs and other cells. Furthermore, in the absence of TLR3, the T lymphocyte response was shifted toward a Th17 profile, which was previously reported to be deleterious for the host. TLR3-deficient mice were very susceptible to CVB3 infection, with increased pancreatic injury and extensive inflammatory infiltrate in the heart that was associated with uncontrolled viral replication. Adoptive transfer of TLR3+ dendritic cells slightly improved the survival of TLR-deficient mice following CVB3 infection. Therefore, our findings highlight the importance of TLR3 signaling in DCs and in other cells to induce activation and polarization of the CD4+ T lymphocyte response toward a Th1 profile and consequently for a better outcome of CVB3 infection. These data provide new insight into the immune-mediated mechanisms by which CVBs are recognized and cleared in order to prevent the development of myocarditis and pancreatitis and may contribute to the design of therapies for enteroviral infections.
B 型柯萨奇病毒（CVB）是急性和慢性心肌炎、脑膜炎及胰腺炎的常见病因，常导致心力衰竭和胰腺功能不全。CD4 + T 淋巴细胞的极化及其细胞因子环境是 CVB 诱导疾病转归的关键因素。因此，感知病毒并驱动适应性免疫反应对于建立保护性免疫反应至关重要。TLR3 是一种关键的病毒识别受体，赋予宿主抵抗 CVB 感染的能力。在本研究中，我们发现树突状细胞中 TLR3 的表达在体外 CVB3 感染时对其激活起作用，因为 TLR3 缺陷的树突状细胞上调 CD80 和 CD86 的程度低于野生型细胞。相反，它们上调了抑制性分子 PD - L1，并分泌了显著更低水平的 TNF -α和 IL - 10，以及更高水平的 IL - 23。与表达 TLR3 的树突状细胞和其他细胞共培养时，CVB3 感染的树突状细胞可促进 T 淋巴细胞增殖。此外，在缺乏 TLR3 的情况下，T 淋巴细胞反应向 Th17 型转变，此前报道这种转变对宿主有害。TLR3 缺陷小鼠对 CVB3 感染非常敏感，胰腺损伤增加，心脏有广泛的炎症浸润，这与病毒复制失控有关。过继转移 TLR3 + 树突状细胞可略微提高 TLR 缺陷小鼠在 CVB3 感染后的存活率。因此，我们的研究结果突出了 TLR3 信号在树突状细胞和其他细胞中对于诱导 CD4 + T 淋巴细胞反应向 Th1 型激活和极化的重要性，从而对于 CVB3 感染有更好的转归。这些数据为柯萨奇病毒被识别和清除以预防心肌炎和胰腺炎发生的免疫介导机制提供了新的见解，并可能有助于设计肠道病毒感染的治疗方法。
