MHC Class I Antigen Presentation in Viral Infections

我们以前已经证明，骨髓来源的专职抗原呈递细胞（pAPC）是 对于引发针对几种病毒的CD8+ T细胞应答至关重要。然而，细胞类型和机制 由此引发这些抗病毒应答的问题仍然没有解决。目前的模型，主要是从 用非感染性抗原（Ags）进行的实验，提出树突状细胞携带来自感染组织的Ags 至次级淋巴器官（SLO），其中CD8+ T细胞被引发。我们认为这种模式也是 这是过于简单的，不能解释所有抗病毒CD8+ T细胞应答的引发。此外，该模型 没有说明感染组织中的pAPC是否必须被病毒感染并迁移 然后直接引发反应，还是必须避免自身感染并获得病毒抗原 从其他受感染的细胞中分离出来，以保持其迁移能力。在这种情况下，交叉呈现可能是 启动的主要机制。另一种可能性是pAPC可能不需要转运病毒， 抗原到SLO，但被感染或获得病毒抗原时，他们已经在SLO。在这种情况下， 组织中未感染的pAPC可以感知感染，并迅速迁移到SLO，等待感染的到来。 病毒我们的假设是，为了最小化免疫逃避，Ag呈递是一个灵活的系统， 可以使用这些机制中的任何一种来适应入侵病毒的类型和感染途径。 在本项目中，我们将使用VACV和LCMV作为我们的模型病毒，用以下方法来检验这一假设 具体目标： 具体目的1：确定并比较巨噬细胞和DC迁移至继发性巨噬细胞的能力。 病毒感染期间的淋巴器官。 具体目的2：确定巨噬细胞和DC对初次抗病毒免疫的细胞的预充和交叉预充能力。 体内CD8+ T细胞。 具体目的3：确定骨髓来源的pAPC在记忆性CD8+ T细胞活化中的作用。 细胞 这些实验应该为理解病毒感染的发病机制提供重要信息 以及诱导抗病毒CD8+ T细胞应答。

We have previously shown that bone marrow-derived professional antigen presenting cells (pAPC) are essential to prime CD8+ T cell responses against several viruses. However, the cell types and mechanisms whereby these anti-viral responses are primed are still unsolved. The current model, mostly inferred from experiments with non-infectious antigens (Ags), proposes that dendritic cells carry Ags from infected tissues to secondary lymphoid organs (SLO) where CD8+ T cells are primed. We think that this model is too simplistic and cannot account for the priming of all anti-viral CD8+ T cell responses. Furthermore, this model does not address whether the pAPC in the infected tissues must become infected with the virus and migrate thereafter to directly prime the responses, or whether it must avoid its own infection and acquire the viral Ags from other infected cells in order to maintain its migratory capacity. In this case cross-presentation could be the major mechanism involved in priming. Another possibility is that pAPC may not need to transport viral Ags to SLO but become infected or acquire the viral Ags when they are already in the SLO. In this scenario, uninfected pAPC in the tissues could sense infection, and rapidly migrate to SLO to wait for the arrival of the virus. Our hypothesis is that, in order to minimize immune evasion, Ag presentation is a flexible system that could use any of these mechanisms in order to adapt to the type of invading virus and the route of infection. In this project we will test this hypothesis using VACV and LCMV as our model viruses with the following specific Aims: Specific Aim 1: To determine and compare the ability of macrophages and DC to migrate to secondary lymphoid organs during viral infections. Specific Aim 2: To determine the ability of macrophages and DC to prime and cross-prime anti-viral naive CD8+ T cells in vivo. Specific Aim 3: To determine the role of bone marrow-derived pAPC in the activation of memory CD8+ T cells. These experiments should provide important information to understand the pathogenesis of viral infections and the induction of anti-viral CD8+ T cell responses.