Usp18 driven enforced viral replication in dendritic cells contributes to break of immunological tolerance in autoimmune diabetes.
Usp18 driven enforced viral replication in dendritic cells contributes to break of immunological tolerance in autoimmune diabetes.
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DOI：
10.1371/journal.ppat.1003650
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发表时间：
2013-10
期刊：
影响因子：
6.7
通讯作者：
Lang KS
中科院分区：
文献类型：
--
作者：
Honke N;Shaabani N;Zhang DE;Iliakis G;Xu HC;Häussinger D;Recher M;Löhning M;Lang PA;Lang KS
携带交叉反应性抗原的病毒感染与免疫耐受的破坏和自身免疫性疾病的诱导有关。树突状细胞在这一过程中起着重要作用。然而，目前尚不清楚为什么自身免疫耐受在病毒感染期间被破坏，而通常在暴露于非复制交叉反应性抗原期间不会被破坏。在这里，我们表明抗原来源于复制病毒，而不是来自非复制源，在脾脏和淋巴结的树突状细胞中经历了增殖过程。这种强制的病毒复制依赖于Usp18，对于自身反应性CD8+ T细胞的扩增是必不可少的。通过消耗CD11c+细胞、基因上删除Usp18或药理学上抑制病毒复制来防止强制病毒复制，可以减弱自身反应性CD8+ T细胞的扩增并预防自身免疫性糖尿病。综上所述，usp18驱动的树突状细胞中病毒的强制复制可以打破免疫耐受，并对自身免疫的诱导产生重要影响。人类自身免疫性糖尿病与病毒感染有关，病毒携带交叉反应性抗原。病毒衍生的交叉反应性抗原打破了对胰岛的免疫耐受性，从而引发疾病。交叉反应性抗原的其他几种非病毒来源是已知的，但它们通常不能诱发糖尿病。在这里，我们发现病毒抗原在树突状细胞中进行Usp18依赖的复制。这一机制对于产生足量的交叉反应性抗原和扩增自身反应性CD8+ T细胞至关重要。通过耗尽树突状细胞、基因耗尽Usp18或药物抑制复制来阻断病毒复制，可使自身反应性CD8+ T细胞的扩增变得迟钝，从而预防糖尿病。总之，我们发现强制病毒复制打破了对自身抗原的耐受性，这部分解释了自身免疫性疾病与病毒感染的强烈关联。
Infection with viruses carrying cross-reactive antigens is associated with break of immunological tolerance and induction of autoimmune disease. Dendritic cells play an important role in this process. However, it remains unclear why autoimmune-tolerance is broken during virus infection, but usually not during exposure to non-replicating cross-reactive antigens. Here we show that antigen derived from replicating virus but not from non-replicating sources undergoes a multiplication process in dendritic cells in spleen and lymph nodes. This enforced viral replication was dependent on Usp18 and was essential for expansion of autoreactive CD8+ T cells. Preventing enforced virus replication by depletion of CD11c+ cells, genetically deleting Usp18, or pharmacologically inhibiting of viral replication blunted the expansion of autoreactive CD8+ T cells and prevented autoimmune diabetes. In conclusion, Usp18-driven enforced viral replication in dendritic cells can break immunological tolerance and critically influences induction of autoimmunity. Autoimmune diabetes in humans is linked to infection with viruses, which carry cross-reactive antigens. Virus derived cross-reactive antigens break immunological tolerance to pancreatic islets, which initiates disease. Several other non-viral sources of cross-reactive antigens are known, however they usually fail to induce diabetes. Here we found that viral antigen underwent an Usp18 dependent replication in dendritic cells. This mechanism was essential to generate sufficient amounts of cross-reactive antigen and to expand autoreactive CD8+ T cells. Blocking of virus replication by either depletion of dendritic cells, genetic depletion of Usp18 or pharmacological inhibition of replication blunted expansion of autoreactive CD8+ T cells and prevented diabetes. In conclusion we found that enforced virus replication broke the tolerance to self-antigen, which partially explains the strong association of autoimmune diseases with virus infections.
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