MHC Class I Antigen Presentation in Viral Infections

我们先前已经证明，骨髓来源的专业抗原提呈细胞(PAPC)是 对于激发CD8 T细胞对几种病毒的反应是必不可少的。然而，细胞类型和机制 这些抗病毒反应是如何启动的仍未解决。当前的模型，主要是从 对非感染性抗原(AGS)的实验表明，树突状细胞携带来自受感染组织的AGS 至次级淋巴器官(SLO)，CD8 T细胞在那里被激活。我们认为这个型号太 过于简单，不能解释所有抗病毒CD8 T细胞反应的启动。此外，该模型还具有较高的效率 没有涉及感染组织中的pAPC是否必须感染病毒并迁移 之后，直接启动反应，或者是否必须避免自身感染并获得病毒AGS 从其他感染细胞中分离出来，以保持其迁移能力。在这种情况下，交叉演示可能是 启动过程中的主要机制。另一种可能性是pAPC可能不需要运输病毒 AGS到SLO，但当他们已经在SLO中时，他们会被感染或获得病毒AGS。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 病毒。我们的假设是，为了最大限度地减少免疫逃避，抗原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。 在这个项目中，我们将使用VACV和LCMV作为我们的模型病毒，并使用以下病毒来验证这一假设 具体目标： 具体目标1：测定和比较巨噬细胞和DC向次级细胞迁移的能力 病毒感染期间的淋巴器官。 特定目标2：确定巨噬细胞和DC启动和交叉启动抗病毒幼稚的能力 体内CD8T细胞。 特异性目标3：确定骨髓源性pAPC在记忆性CD8 T激活中的作用 细胞。 这些实验应该为了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细胞反应。

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.