Cellular Immunoregulation Group, Department of Dermatology and Allergology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
Deutsches Rheuma-Forschungszentrum Berlin, 10117 Berlin, Germany.
Sci Transl Med. 2014 Jun 18;6(241):241ra80. doi: 10.1126/scitranslmed.3008706.
Although T helper 17 (TH17) 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 TH17 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 TH cell subsets. Surprisingly, the induction of GM-CSF expression by human TH cells is constrained by the interleukin-23 (IL-23)/ROR-γt/TH17 cell axis but promoted by the IL-12/T-bet/TH1 cell axis. IL-2-mediated signal transducer and activator of transcription 5 (STAT5) signaling induced GM-CSF expression in naïve and memory TH cells, whereas STAT3 signaling blocked it. The opposite effect was observed for IL-17 expression. Ex vivo, GM-CSF(+) TH cells that coexpress interferon-γ and T-bet could be distinguished by differential chemokine receptor expression from a previously uncharacterized subset of GM-CSF-only-producing TH cells that did not express TH1, TH2, and TH17 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 TH17 but instead with the TH1 axis.
尽管辅助性 T 细胞 17（TH17）细胞已被认为是自身免疫性组织损伤的关键介质，但负责其致病性的效应细胞因子仍未得到明确界定，尤其是在人类中。在自身免疫性疾病的小鼠模型中，TH17 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。我们分析了人类 TH 细胞亚群对 GM-CSF 表达的调节。令人惊讶的是，人类 TH 细胞 GM-CSF 表达的诱导受到白细胞介素 23（IL-23）/ROR-γt/TH17 细胞轴的限制，但受到白细胞介素 12（IL-12）/T 细胞因子结合蛋白（T-bet）/TH1 细胞轴的促进。IL-2 介导的信号转导和转录激活因子 5（STAT5）信号诱导初始和记忆 TH 细胞中 GM-CSF 的表达，而 STAT3 信号则阻断其表达。对 IL-17 表达则观察到相反的效果。在体外，通过差异趋化因子受体表达，可以将共表达干扰素-γ和 T 细胞因子结合蛋白的 GM-CSF（+）TH 细胞与以前未表征的仅产生 GM-CSF 的 TH 细胞亚群区分开来，后者不表达 TH1、TH2 和 TH17 特征细胞因子或主转录因子。我们的研究结果表明，产生 IL-17 和 GM-CSF 细胞的途径是不同的和相互拮抗的，并且还表明 GM-CSF（+）T 细胞在多发性硬化症（MS）患者的炎症大脑中具有致病性作用。这不仅为在 MS 患者中耗尽 T 细胞衍生的 GM-CSF 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，这些检查点与 TH17 不同，而是与 TH1 轴相关。
