Human Lung T cell subsets in Disease

摘要 特发性肺纤维化(IPF)是一种原因不明的进行性和致命性肺部疾病，其影响范围超过 美国有12.8万人。确诊后的中位生存期为2-3年，比许多癌症都要差。 IPF中不可逆转的纤维化被经典地认为是异常信号通路的最终结果，包括 肺泡上皮细胞和间质成纤维细胞。而免疫系统在IPF发病机制中的作用 仍然存在争议，最近的一项研究发现，T细胞特异性基因表达可以预测IPF的预后 这意味着活动性进展性疾病患者的T细胞发生了潜在的变化。T 根据细胞因子的产生，细胞可以被划分为不同的功能亚集。因此，中的变化 IPF T细胞基因表达可反映这些亚群的数量和/或质的变化。 了解特发性肺纤维化患者肺中存在的不同T细胞亚群可能解释为什么 当然，病程的存在以及确定潜在的新的治疗靶点。在此应用程序中，我们呈现 令人兴奋的初步数据表明，IPF肺中存在CD4T细胞表型的显著变化 组织和肺引流淋巴结(LLN)，这些变化与疾病进展相关。我们 我比较了移植肺组织中的CD4T细胞和9名IPF患者肺组织中的LN 移植来自13个年龄和性别匹配的供体肺和LLN的T细胞，这些供体肺不适合 移植(伊利诺伊州希望地区器官银行慷慨捐赠；Goh/Robi)。使用这些 样本中，我们发现IPF患者CD4T细胞上趋化因子受体的表达不同。 戏剧性地来自GOG/Robi捐赠者的肺。在血液中，趋化因子受体被用来识别 功能不同的CD4T细胞亚群。趋化因子受体是否指定特定的CD4T细胞亚群 在呼吸道组织中的作用是未知的，也是这一应用的一个主要目的。因此，我们的中心假设是 CD4T细胞亚群在IPF发病过程中的功能改变导致其细胞因子的变化 血液、肺和肺组织中的模式。这些研究的长期目标是阐明改变的T细胞 特发性肺纤维化患者的免疫反应，这种反应如何随时间变化，以及它是否与 肺功能下降。在本研究中，我们建议阐明趋化因子受体的表达是否决定了 IPF患者肺内不同功能的CD4亚群和LLN，并确定CD4T 一组IPF患者血液中的细胞亚群和T细胞因子随着时间的推移而变化。完成 这些研究将提供有关这些差异的程度和潜力的基本知识 这些差异在IPF病理中的作用机制。改变的T细胞是否是对 纤维化或导致纤维化，了解细胞成分的基于位置的差异，以及 外周T细胞细胞因子随时间的变化，将有助于深入了解关键T细胞亚群在IPF中的作用 进步。

ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown cause that affects over 128,000 people in the United States. Median survival from diagnosis is 2-3 yrs, worse than many cancers. Irreversible fibrosis in IPF is classically thought to be the end result of abnormal signaling pathways involving alveolar epithelial cells and interstitial fibroblasts. While the role of the immune system in IPF pathogenesis remains controversial, a recent study has found that T cell specific gene expression predicts outcomes in IPF patients, thereby implicating an underlying change in T cells in patients with actively progressive disease. T cells can be divided into distinct functional subsets based on their cytokine production. As such, the changes in IPF T cell gene expression could reflect quantitative and/or qualitative changes in these subsets. Understanding the distinct subsets of T cells present in the lungs of IPF patients may explain why the variability of disease course exists as well as identify potential novel therapeutic targets. In this application, we present exciting preliminary data suggesting that striking alterations in CD4 T cell phenotypes exist within IPF lung tissue and lung draining lymph nodes (LLN) and that these alterations correlate with disease progression. We have compared CD4 T cells from explanted lung tissue and LLN from 9 subjects with IPF who underwent lung transplantation to T cells from 13 age and gender matched donor lungs and LLN that were not suitable for transplant (generous donation from Gift of Hope Regional Organ Bank of Illinois; GOH/ROBI). Using these samples, we have found that chemokine receptor expression on CD4 T cells from IPF patients differ dramatically from GOG/ROBI donor lungs. In the blood, chemokine receptors have been used to identify functionally distinct CD4 T cell subsets. Whether chemokine receptors designate specific CD4 T cell subsets in respiratory tissues is unknown and is a major objective of this application. Thus, our central hypothesis is that CD4 T cell subsets are functionally altered during IPF pathogenesis resulting in changes in their cytokine patterns within the blood, lung and LLN. The long-term goal of these studies is to elucidate the altered T cell immune response in patients with IPF, how this response changes over time, and whether it is associated with declining lung function. In this study, we propose the to elucidate if chemokine receptor expression determines functionally different CD4 subsets within the lungs and LLN in patients with IPF, and to determine how CD4 T cell subsets and T cell cytokines in the blood of a cohort of patients with IPF change over time. Completion of these studies will provide essential knowledge about the extent of these differences and the potential mechanisms by which these differences contribute to IPF pathology. Whether altered T cells are a response to fibrosis or contributing to fibrosis, understanding the location-based differences in cellular compositions, and changes in peripheral T cell cytokines over time, will provide insight into the role of key T cell subsets in IPF progression.