Pane Jessica A, Webster Nicole L, Coulson Barbara S
Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria, Australia.
PLoS Pathog. 2014 Mar 27;10(3):e1003998. doi: 10.1371/journal.ppat.1003998. eCollection 2014 Mar.
It has been proposed that rotavirus infection promotes the progression of genetically-predisposed children to type 1 diabetes, a chronic autoimmune disease marked by infiltration of activated lymphocytes into pancreatic islets. Non-obese diabetic (NOD) mice provide a model for the human disease. Infection of adult NOD mice with rhesus monkey rotavirus (RRV) accelerates diabetes onset, without evidence of pancreatic infection. Rather, RRV spreads to the pancreatic and mesenteric lymph nodes where its association with antigen-presenting cells, including dendritic cells, induces cellular maturation. RRV infection increases levels of the class I major histocompatibility complex on B cells and proinflammatory cytokine expression by T cells at these sites. In autoimmunity-resistant mice and human mononuclear cells from blood, rotavirus-exposed plasmacytoid dendritic cells contribute to bystander polyclonal B cell activation through type I interferon expression. Here we tested the hypothesis that rotavirus induces bystander activation of lymphocytes from NOD mice by provoking dendritic cell activation and proinflammatory cytokine secretion. NOD mouse splenocytes were stimulated with rotavirus and assessed for activation by flow cytometry. This stimulation activated antigen-presenting cells and B cells independently of virus strain and replicative ability. Instead, activation depended on virus dose and was prevented by blockade of virus decapsidation, inhibition of endosomal acidification and interference with signaling through Toll-like receptor 7 and the type I interferon receptor. Plasmacytoid dendritic cells were more efficiently activated than conventional dendritic cells by RRV, and contributed to the activation of B and T cells, including islet-autoreactive CD8+ T cells. Thus, a double-stranded RNA virus can induce Toll-like receptor 7 signaling, resulting in lymphocyte activation. Our findings suggest that bystander activation mediated by type I interferon contributes to the lymphocyte activation observed following RRV infection of NOD mice, and may play a role in diabetes acceleration by rotavirus.
有人提出，轮状病毒感染会促使具有遗传易感性的儿童发展为1型糖尿病，这是一种慢性自身免疫性疾病，其特征是活化淋巴细胞浸润到胰岛中。非肥胖糖尿病（NOD）小鼠为这种人类疾病提供了一个模型。用恒河猴轮状病毒（RRV）感染成年NOD小鼠会加速糖尿病的发病，且没有胰腺感染的迹象。相反，RRV扩散到胰腺和肠系膜淋巴结，在那里它与包括树突状细胞在内的抗原呈递细胞结合，诱导细胞成熟。RRV感染会增加这些部位B细胞上I类主要组织相容性复合体的水平以及T细胞的促炎细胞因子表达。在抗自身免疫的小鼠和来自血液的人单核细胞中，暴露于轮状病毒的浆细胞样树突状细胞通过I型干扰素表达促进旁观者多克隆B细胞活化。在这里，我们测试了这样一个假设，即轮状病毒通过激发树突状细胞活化和促炎细胞因子分泌来诱导NOD小鼠淋巴细胞的旁观者活化。用轮状病毒刺激NOD小鼠脾细胞，并通过流式细胞术评估其活化情况。这种刺激独立于病毒株和复制能力激活了抗原呈递细胞和B细胞。相反，活化取决于病毒剂量，并且通过阻断病毒脱壳、抑制内体酸化以及干扰通过Toll样受体7和I型干扰素受体的信号传导来阻止。RRV比传统树突状细胞更有效地激活浆细胞样树突状细胞，并促进B细胞和T细胞的活化，包括胰岛自身反应性CD8 + T细胞。因此，一种双链RNA病毒可以诱导Toll样受体7信号传导，导致淋巴细胞活化。我们的研究结果表明，由I型干扰素介导的旁观者活化促成了RRV感染NOD小鼠后观察到的淋巴细胞活化，并且可能在轮状病毒加速糖尿病的过程中起作用。
