Interferon gamma-Producing Th17 Subsets: Major Contributors to "Th1" Diseases

摘要：我们最近在两个不同的队列中发现，最普遍的免疫细胞 肺结节病肺灌洗液中产生干扰素γ(干扰素γ)的不是Th1细胞，而是另一种具有 被鉴定为Th17细胞的一个高致病性亚群，称为Th17.1，因为它们具有增强的 除其他功能外，还可产生干扰素γ。这些发现挑战了Th1范式，该范式在 结节病自发明支气管镜检查以来一直在研究。但更重要的是，我们的发现有能力 将研究重点转移到这些Th17.1细胞上，我们对它们的致病特性和 结节病患者与Th17细胞的功能差异。文献表明Th17.1细胞出现了 从经典极化的Th17细胞衍生而来，这种细胞具有高度的可塑性，可以被刺激打开 促炎症细胞因子如IL-12对Th1相关信号通路的影响。结节病中的Th17.1细胞不 似乎与记录的Th17细胞的增殖缺陷相同。我们还从克罗恩病中得知， TH17.1细胞表现出皮质类固醇耐药。在我们的数据中，我们发现了一种趋势，即 肺功能(预计FEV1%)和Th17.1细胞百分比增加。这表明Th17.1细胞在 结节病可能与疾病的严重程度有关，但细胞机制尚未被探索。此外, 在已发表的研究中发现了Th17系细胞的另一种不同的亚群，称为“Th17- 衍生的Th1细胞“。这些细胞被认为比Th17.1更倾向于Th1表型 细胞由于失去IL-17A分泌和显著产生干扰素γ所致。因此，我们对高频的发现 Th17.1细胞在结节病中的表达提出了这样一个问题：在结节病中我们一直称之为“Th1”的细胞 实际上可能属于Th17派生的Th1子集。因此，我们假设Th17细胞是 可塑性及其生物学表型存在于连续统体中，来源于Th17Th17.1→→Th17来源的Th1细胞 结节病中存在极化细胞因子IL-12和干扰素γ的环境。这些极化的Th17细胞具有致病作用 有可能促进结节样炎症并导致进行性疾病。因此，我们建议审问 结节病患者Th17和Th17.1细胞增殖能力及相关功能的比较 对照组和哮喘患者。我们还将使用流式细胞术和细胞周期图方法来测量Th17的范围 亚群及其抵抗皮质类固醇效应的能力。

Abstract: We have recently discovered in two separate cohorts that the most prevalent immune cells producing interferonγ (IFNγ) in pulmonary sarcoidosis lung lavage are not Th1 cells but another cell which has been identified as a highly pathogenic subset of Th17 cells, called Th17.1, due to their enhanced ability to produce IFNγ among other functions. These findings challenge the Th1 paradigm that has held sway in sarcoidosis since the invention of research bronchoscopy. But more importantly, our findings have the ability to shift the research focus to these Th17.1 cells, about which we know little of their pathogenic traits and functional differences compared to Th17 cells in sarcoidosis. The literature suggests that Th17.1 cells appear to be derived from classically polarized Th17 cells which are highly “plastic” and can be stimulated to turn on Th1-related signaling pathways by proinflammatory cytokines such as IL-12. Th17.1 cells in sarcoidosis do not appear to share proliferative defects as documented for Th17 cells. We also know from Crohn's disease that Th17.1 cells exhibit corticosteroid resistance. In our data, we found a trend in correlation between worsening lung function (FEV1 % predicted) with increasing percentage of Th17.1 cells. This suggests that Th17.1 cells in sarcoidosis may contribute to disease severity but cellular mechanisms have not been explored. In addition, another distinct subset of Th17 linage cells have been identified in published studies and are called “Th17- derived Th1 cells”. These cells are thought to be even more polarized towards a Th1 phenotype than Th17.1 cells due to their loss of IL-17A secretion and marked production of IFNγ. Thus, our finding of high frequencies of Th17.1 cells in sarcoidosis raises the question of whether the cells we have long termed “Th1” in sarcoidosis could actually instead belong to this Th17-derived Th1 subset. Therefore, we hypothesize that Th17 cells are plastic and their biologic phenotype exists in a continuum from Th17→Th17.1→Th17-derived Th1 cells in the milieu of polarizing cytokines IL-12 and IFNγ found in sarcoidosis. These polarized Th17 cells have pathogenic potential to promote sarcoidal inflammation and cause progressive disease. Thus, we propose to interrogate the proliferative capacity and related functions of Th17 vs Th17.1 cells in sarcoidosis compared healthy controls and asthmatics. We will also use flow cytometry and CyTOF methods to measure the range of Th17 subsets and their ability to resist corticosteroid effects.