Role of PD1 blockade and IL-10 during infection in aging

项目总结 老年人感染死亡的风险很高，流感和肺炎一直位居 这是美国65岁以上人群的头号死因。在中国，混合感染率也有所上升。 老年人住进ICU与住院死亡率有关。有必要采用新的方法 使衰老的免疫系统恢复活力，促进感染的控制。我们利用一项实验性的 使实验小鼠接触多种微生物的范例(称为正常微生物体验；NME)。 NME能激活小鼠的免疫系统，增加功能性记忆T细胞。然而，在老年老鼠身上， 接触NME会导致100%的死亡，在此之前会出现细胞因子风暴和免疫渗透增加 在多个组织中。现有证据表明，免疫衰老，包括炎症和 免疫系统功能障碍，在老年人感染的发病中起着因果作用。疲惫是一种细胞 老年人淋巴细胞中的命运增加，这有助于炎症、病毒 持久性和组织病理学。它主要是通过慢性抗原暴露来强制执行，但也受到 局部分泌因子，如年轻人体内的IL-10。目前尚不清楚具体因素是如何控制疲劳的。 在老年人感染之前和感染期间。我们推测，IL-10，一种传统的抗炎药物 随着年龄的增长而积累的细胞因子，对CD8 T细胞也有促细胞毒作用，是一种调节 随着年龄的增长而筋疲力尽。这项建议是基于我们令人兴奋的初步数据，这些数据描述了PD1的效果 阻断，它通过恢复T细胞激活来减少疲惫，并将IL-10牵涉到这一反应中。基座 根据我们的数据，我们想知道：IL-10是促进还是防止精疲力竭？我们假设PD1封锁 以IL-10/IL-10R依赖的方式缓解CD8+T细胞耗竭。我们将使用实验范式 以检验这一假说。目的1确定IL-10/IL-10R在支持T细胞中的作用 在衰老过程中发挥作用。AIM2是为了确定IL-10支持老年人T细胞功能的机制 老鼠。

PROJECT SUMMARY The elderly are at high risk for mortality to infection, with influenza and pneumonia consistently ranked among the top leading causes of death in the US for those over 65. There is also an increased rate of co-infections in the elderly admitted to the ICU that is associated with hospital mortality. There is a need for novel approaches that rejuvenate the aged immune system to promote the control of infection. We leverage an experimental paradigm that exposes experimental mice to multiple microbes (termed normal microbial experience; NME). NME activates the immune system in young mice, increasing functional memory T cells. However, in old mice, NME-exposure leads to 100% mortality that is preceded by a cytokine storm and increased immune infiltrates in multiple tissues. Existing evidence demonstrates that immunosenescence, including inflammaging and the dysfunctional immune system, play a causal role in morbidity to infections in the elderly. Exhaustion is a cell fate that is increased in lymphocytes from the elderly, and which contributes to inflammaging, virus persistence, and tissue pathology. It is primarily enforced by chronic antigen exposure, but also regulated by local secreted factors, like IL-10 in younger individuals. It is unknown how specific factors control exhaustion prior to and during infection in older individuals. We speculate that IL-10, a traditional anti-inflammatory cytokine that accumulates with age, and which also has pro-cytotoxic effects on CD8 T cells, is a regulator of exhaustion with age. This proposal is based on our exciting preliminary data which describes the effect of PD1 blockade, which reduces exhaustion by restoring T cell activation and implicates IL-10 in that response. Based on our data, we wonder: does IL-10 promotes exhaustion or prevents it? We hypothesize that PD1 blockade relieves CD8+ T cell exhaustion in an IL-10/IL-10R dependent manner. We will use the experimental paradigm of NME-exposure to test this hypothesis. Aim 1 is to establish the role for IL-10/IL-10R in supporting T cell function during aging. Aim2 is to determine the mechanism by which IL-10 supports T cell function in aged mice.