Targeting Inhibitory T cell Receptors for PcP Therapy

 描述(由申请人提供)：肺孢子虫肺炎(PCP)仍然是免疫功能低下患者发病和死亡的重要原因。尽管有有效的预防措施，但美国每年都会发生5000-10000个病例，全世界都有超过40万个病例。PCP的死亡率为10%-20%，有数千人死亡，发病率很高。此外，需要呼吸机支持的患者的死亡率为50%甚至更高。因此，确实需要新的治疗策略，在没有炎症和损伤的情况下快速根除有机体。在这项探索性/发展性拨款中，我们建议确定抑制性T细胞受体的激活是否限制了CD8+T细胞在CD4功能受损的宿主中对抗PC感染的能力。在没有CD4细胞的情况下，招募到肺部的CD8+T细胞群体缺乏效应活性，甚至可能抑制剩余的肺免疫，从而使Pc生长和疾病进展。然而，也有研究表明，在没有CD4+T细胞的情况下，CD8+T细胞可以被激活以根除PC感染。我们发现，在PC感染期间，大多数CD8+T细胞被招募到肺部，表达抑制性受体PD-1，这也是T细胞耗竭的标志。PD-1信号通路抑制T效应分子的功能，对Treg功能也很重要。因此，我们假设慢性PC感染肺中的CD8细胞采用耗尽和/或抑制表型，这限制了这些细胞的宿主防御功能。通过阻断抑制性受体信号，我们相信可以挽救这些细胞，恢复效应器功能。这项探索性/发展性拨款的总体目标是确定T细胞抑制受体是否限制了CD8+T细胞的抗PC效应功能，并有助于CD4+T细胞功能受损的宿主的免疫抑制肺环境。为了实现这一目标，我们将完成以下具体目标：1)确定在PCP过程中抑制性受体的表达是否定义了不同的CD8+T细胞亚群；2)确定抑制性受体阻断是否恢复了CD8+T细胞的效应功能和抗PC宿主防御。这项拟议的研究将增强我们对宿主防御PC感染的理解，并有可能导致新的治疗策略，这些策略可以转化为改善患者状况 关心。

 DESCRIPTION (provided by applicant): Pneumocystis pneumonia (PcP) remains an important cause of morbidity and mortality among immune compromised patients. Despite the availability of effective prophylaxis, each year 5,000-10,000 cases occur in the U.S. and more than 400,000 cases occur worldwide. With a mortality rate of 10-20% there are thousands of deaths and significant morbidity as a result of PCP. Furthermore, patients requiring ventilator support have a mortality rate of 50% or even higher. Therefore, there is a definite need for novel therapeutic strategies that quickly eradicate the organism in the absence of inflammation and injury. In this exploratory/developmental grant, we propose to determine whether activation of inhibitory T cell receptors limits the ability of CD8+ T cells to fight PC infection in hosts with impaired CD4 function. In the absence of CD4 cells, the CD8+ T cell population recruited to the lungs lacks effector activity and may even suppress residual lung immunity allowing, Pc to grow and disease to progress. However, it has also been demonstrated that CD8+ T cells can be activated to eradicate PC infection in the absence CD4+ T cells. We have found that the majority of CD8+ T cells recruited to the lungs during PC infection express the inhibitory receptor PD-1, which is also a marker of T cell exhaustion. PD-1 signaling inhibits T effector function and is also important for Treg function. Thus, we hypothesize that CD8 cells in the lungs of chronically PC-infected lungs adopt an exhausted and/or suppressor phenotype, which limits the host defense function of these cells. By blocking inhibitory receptor signaling we believe that these cells can be rescued and effector function restored. The overall goal of this exploratory /developmental grant is to determine whether T cell inhibitory receptors limit the anti-PC effector function of CD8+ T cells and contribute to an immunosuppressive lung environment in hosts with impaired CD4+ T cell function. To accomplish this goal we will complete the following Specific Aims: 1) To determine whether inhibitory receptor expression defines functionally distinct CD8+ T cell subsets during PcP; 2) To determine whether inhibitory receptor blockade restores CD8+ T cell effector function and anti-PC host defense. The proposed research will enhance our understanding of host defense against PC infection, and has the potential to lead to novel therapeutic strategies that can be translated to improve patient care.