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Regulation and role of GM-CSF production by human T helper cells in health and inflammation

人类 T 辅助细胞产生 GM-CSF 在健康和炎症中的调节和作用

基本信息

批准号：
233380263
负责人：
Professorin Dr. Christina Zielinski
金额：
--
依托单位：
Abteilung Infektionsimmunologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/233380263?language=en
关键词：
Regulation role GM CSF production

项目摘要

T helper cells represent a growing family of specialized immune cell subsets that differ in their cytokine profile, migration properties and antigen targets. Th17 cells joined this family as a T helper cell lineage with major pathogenic functions in autoimmunity a few years ago. We have recently demonstrated the existence of two types of human Th17 cells with pro- and anti-inflammatory cytokine profiles. Anti-inflammatory Th17 cells co-produced IL-10 whereas pro-inflammatory Th17 cells co-produced IFN-gamma. They not only differed in function but also in priming requirements and pathogen specificities. These findings have revealed unexpected heterogeneity within the Th17 cell subset with implications for their role in health and disease.GM-CSF has recently been identified as a crucial pathogenic cytokine of the Th17 cell lineage for autoimmunity in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. It has even been shown to be more relevant for EAE pathogenesis than IL-17, which has so far been considered the Th17 signature cytokine. This suggests Th17 cell derived GM-CSF to be a promising therapeutic target in settings of inflammation. However, its expression, regulation and role in human T helper cells in health and disease have not been studied. Considering its pathogenic role in mice, a detailed characterization of GM-CSF regulation in human T cells will be important to provide a scientific basis for therapeutic targeting strategies. We therefore aim to identify and characterize GM-CSF producing T helper cells in humans. Our preliminary data demonstrate that GM-CSF can be expressed in T helper cells independently of IL-17 and also of any other lineage defining cytokine such as IFN-gamma, IL-4. This suggests the existence of GM-CSF-only producing T helper cells. We will study the requirements for their generation, their stability and plasticity, their migration properties as well as the transcriptional regulation of GM-CSF production in human T helper cells. We will also analyze whether the TCR repertoire of GM-CSF producing T helper cells differs from that of Th1, Th2 and Th17 cell subsets by using a novel method that allows the large-scale interrogation of the human TCR repertoire by using libraries of amplified T cells. This approach is based on the proliferation of antigen specific T helper cells in response to pathogen derived antigens and autoantigens. These studies will for the first time provide a characterization of human GM-CSF producing T helper cells and will determine whether a specialized GM-CSF producing subset with unique functions and phenotypic properties that differs from the classical T helper subsets exists. The proposed project will provide a scientific basis for therapeutic targeting of this cytokine in infections and autoimmune diseases.

辅助性T细胞代表了一个不断增长的专门的免疫细胞亚群的家庭，不同的细胞因子谱，迁移特性和抗原的目标。几年前，Th 17细胞作为辅助性T细胞谱系加入该家族，在自身免疫中具有主要致病功能。我们最近已经证明了存在两种类型的人Th 17细胞与促炎和抗炎细胞因子谱。抗炎性Th 17细胞共产生IL-10，而促炎性Th 17细胞共产生IFN-γ。它们不仅在功能上不同，而且在引发要求和病原体特异性上也不同。这些发现揭示了Th 17细胞亚群中意想不到的异质性，暗示了它们在健康和疾病中的作用。GM-CSF最近被鉴定为在多发性硬化症的实验性自身免疫性脑脊髓炎（EAE）小鼠模型中自身免疫的Th 17细胞谱系的关键致病细胞因子。它甚至被证明比IL-17更与EAE发病机制相关，IL-17迄今为止被认为是Th 17标志性细胞因子。这表明Th 17细胞衍生的GM-CSF是炎症环境中有希望的治疗靶点。然而，其在健康和疾病中的人类T辅助细胞中的表达、调节和作用尚未被研究。考虑到其在小鼠中的致病作用，对人T细胞中GM-CSF调节的详细表征对于为治疗靶向策略提供科学依据将是重要的。因此，我们的目标是确定和表征GM-CSF生产T辅助细胞在人类。我们的初步数据表明，GM-CSF可以在T辅助细胞中独立于IL-17和任何其他谱系定义细胞因子如IFN-γ、IL-4表达。这表明存在仅产生GM-CSF的T辅助细胞。我们将研究其产生的要求，它们的稳定性和可塑性，它们的迁移特性以及在人类T辅助细胞中GM-CSF产生的转录调控。我们还将分析是否产生GM-CSF的T辅助细胞的TCR库不同于Th 1，Th 2和Th 17细胞亚群，通过使用一种新的方法，允许大规模的人类TCR库的询问，通过使用扩增的T细胞库。该方法基于抗原特异性T辅助细胞响应于病原体来源的抗原和自身抗原的增殖。这些研究将首次提供人产生GM-CSF的T辅助细胞的表征，并将确定是否存在具有不同于经典T辅助细胞亚群的独特功能和表型特性的专门的产生GM-CSF的亚群。该项目将为这种细胞因子在感染和自身免疫性疾病中的治疗靶向提供科学依据。