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

翻译后摘要：我们最近发现，在两个不同的队列，最普遍的免疫细胞 在肺结节病肺灌洗液中产生干扰素γ（IFNγ）的不是Th 1细胞，而是另一种细胞， 被鉴定为Th 17细胞的高致病性亚群，称为Th17.1，这是由于它们增强的能力， 产生IFNγ等功能。这些发现挑战了Th 1范式，Th 1范式在人类免疫系统中占主导地位。 自从支气管镜检查发明以来，但更重要的是，我们的发现能够 将研究重点转移到Th17.1细胞，我们对其致病特性知之甚少， 与结节病中的Th 17细胞相比的功能差异。文献表明，Th17.1细胞似乎 来源于经典极化的Th 17细胞，其是高度“可塑的”，并且可以被刺激打开， Th 1相关信号通路通过促炎细胞因子如IL-12。结节病中的Th17.1细胞 似乎共享如Th 17细胞所记录的增殖缺陷。我们还知道克罗恩病 Th17.1细胞表现出皮质类固醇抗性。在我们的数据中，我们发现了一种趋势， 肺功能（FEV1%预测值）随Th17.1细胞百分比增加而增加。这表明，Th17.1细胞在 结节病可能导致疾病的严重程度，但细胞机制尚未探索。此外，本发明还提供了一种方法， 在已发表的研究中已经鉴定了另一种不同的Th 17谱系细胞亚群，称为“Th 17- Th 1细胞”。这些细胞被认为甚至比Th 17更趋向于Th 1表型。 细胞由于其IL-17 A分泌的损失和IFNγ的显著产生而死亡。因此，我们发现的高频率 Th17.1细胞在结节病中的表达提出了一个问题，即我们长期以来在结节病中称为“Th 1”的细胞是否 实际上可能属于Th 17衍生的Th 1亚群。因此，我们假设Th 17细胞是 塑料和它们的生物表型存在于从Th 17 →Th17.1→ Th 17衍生的Th 1细胞的连续体中， 在结节病中发现的极化细胞因子IL-12和IFNγ的环境。这些极化的Th 17细胞具有致病性 可能促进结节性炎症并导致疾病进展。因此，我们建议询问 结节病患者Th 17细胞与Th17.1细胞的增殖能力和相关功能与健康人相比， 对照组和哮喘组。我们还将使用流式细胞术和CyTOF方法来测量Th 17的范围 亚群及其抵抗皮质类固醇作用的能力。

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.