IL-17 and GM-CSF Expression Are Antagonistically Regulated by Human T Helper Cells
IL-17 and GM-CSF Expression Are Antagonistically Regulated by Human T Helper Cells
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DOI：
10.1126/scitranslmed.3008706
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发表时间：
2014-06-18
影响因子：
17.1
通讯作者：
Zielinski, Christina E.
中科院分区：
文献类型：
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作者：
Noster, Rebecca;Riedel, Rene;Zielinski, Christina E.
虽然辅助性T细胞17（T（H）17）被认为是自身免疫性组织损伤的重要介质，但负责其致病性的效应细胞因子仍然不清楚，特别是在人类中。在小鼠自身免疫模型中，T（H）17细胞的致病性最近与它们产生粒细胞-巨噬细胞集落刺激因子（GM-CSF）有关。我们分析了人T-H细胞亚群对GM-CSF表达的调节。令人惊讶的是，人T-H细胞对GM-CSF表达的诱导受到白介素-23（IL-23）/ROR-γ t/T（H）17细胞轴的限制，但受到IL-12/T-bet/T（H）1细胞轴的促进。IL-2介导的信号转导子和转录激活子5（STAT 5）信号通路可诱导幼稚和记忆T-H细胞表达GM-CSF，而STAT 3信号通路则可阻断这种作用，而IL-17的表达则相反。通过趋化因子受体表达的差异，可以在体外将共表达干扰素-g和T-bet的GM-CSF+ T-H细胞与先前未表征的仅产生GM-CSF的T-H细胞亚群（不表达T（H）1、T（H）2和T（H）17特征性细胞因子或主转录因子）区分开来。我们的研究结果证明了IL-17和GM-CSF产生细胞的产生的不同和反调节途径，也表明GM-CSF+ T细胞在多发性硬化症（MS）患者的炎症脑中的致病作用。这不仅为MS患者中T细胞来源的GM-CSF的耗竭提供了科学依据，而且为治疗性GM-CSF抑制提供了多个新的分子检查点，与小鼠不同，这些检查点与T（H）17无关，而是与T（H）1轴相关。
Although T helper 17 (T(H)17) cells have been acknowledged as crucial mediators of autoimmune tissue damage, the effector cytokines responsible for their pathogenicity still remain poorly defined, particularly in humans. In mouse models of autoimmunity, the pathogenicity of T(H)17 cells has recently been associated with their production of granulocyte-macrophage colony-stimulating factor (GM-CSF). We analyzed the regulation of GM-CSF expression by human T-H cell subsets. Surprisingly, the induction of GM-CSF expression by human T-H cells is constrained by the interleukin-23 (IL-23)/ROR-gamma t/T(H)17 cell axis but promoted by the IL-12/T-bet/T(H)1 cell axis. IL-2-mediated signal transducer and activator of transcription 5 (STAT5) signaling induced GM-CSF expression in naive and memory T-H cells, whereas STAT3 signaling blocked it. The opposite effect was observed for IL-17 expression. Ex vivo, GM-CSF+ T-H cells that coexpress interferon-g and T-bet could be distinguished by differential chemokine receptor expression from a previously uncharacterized subset of GM-CSF-only-producing T-H cells that did not express T(H)1, T(H)2, and T(H)17 signature cytokines or master transcription factors. Our findings demonstrate distinct and counterregulatory pathways for the generation of IL-17- and GM-CSF-producing cells and also suggest a pathogenic role for GM-CSF+ T cells in the inflamed brain of multiple sclerosis (MS) patients. This provides not only a scientific rationale for depleting T cell-derived GM-CSF in MS patients but also multiple new molecular checkpoints for therapeutic GM-CSF suppression, which, unlike in mice, do not associate with the T(H)17 but instead with the T(H)1 axis.