Rasouli Javad, Casella Giacomo, Yoshimura Satoshi, Zhang Weifeng, Xiao Dan, Garifallou James, Gonzalez Michael V, Wiedeman Alice, Kus Anna, Mari Elisabeth R, Fortina Paolo, Hakonarson Hakon, Long S Alice, Zhang Guang-Xian, Ciric Bogoljub, Rostami Abdolmohamad
Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, PA, USA.
Sci Immunol. 2020 Oct 23;5(52). doi: 10.1126/sciimmunol.aba9953.
Elevation of granulocyte-macrophage colony-stimulating factor (GM-CSF)–producing T helper (T) cells has been associated with several autoimmune diseases, suggesting a potential role in the pathogenesis of autoimmunity. However, the identity of GM-CSF–producing T cells has not been closely examined. Using single-cell RNA sequencing and high-dimensional single-cell mass cytometry, we identified eight populations of antigen-experienced CD45RACD4 T cells in blood of healthy individuals including a population of GM-CSF–producing cells, known as TGM, that lacked expression of signature transcription factors and cytokines of established T lineages. Using GM-CSF-reporter/fate reporter mice, we show that TGM cells are present in the periphery and central nervous system in a mouse model of experimental autoimmune encephalomyelitis. In addition to GM-CSF, human and mouse TGM cells also expressed IL-2, tumor necrosis factor (TNF), IL-3, and CCL20. TGM cells maintained their phenotype through several cycles of activation but up-regulated expression of T-bet and interferon-γ (IFN-γ) upon exposure to IL-12 in vitro and in the central nervous system of mice with autoimmune neuroinflammation. Although T-bet was not required for the development of TGM cells, it was essential for their encephalitogenicity. These findings demonstrate that TGM cells constitute a distinct population of T cells with lineage characteristics that are poised to adopt a T1 phenotype and promote neuroinflammation.
产生粒细胞-巨噬细胞集落刺激因子（GM-CSF）的辅助性T（Th）细胞水平升高与多种自身免疫性疾病相关，提示其在自身免疫发病机制中可能发挥作用。然而，产生GM-CSF的T细胞的身份尚未得到深入研究。利用单细胞RNA测序和高维单细胞质谱流式细胞术，我们在健康个体血液中鉴定出8个抗原经验丰富的CD45RACD4 T细胞群体，其中包括一个产生GM-CSF的细胞群体，称为TGM，该群体缺乏已确定的T细胞谱系的标志性转录因子和细胞因子的表达。利用GM-CSF报告基因/命运报告基因小鼠，我们发现在实验性自身免疫性脑脊髓炎小鼠模型中，TGM细胞存在于外周和中枢神经系统。除GM-CSF外，人和小鼠的TGM细胞还表达白细胞介素-2（IL-2）、肿瘤坏死因子（TNF）、IL-3和CC趋化因子配体20（CCL20）。TGM细胞通过几个激活周期维持其表型，但在体外和患有自身免疫性神经炎症的小鼠中枢神经系统中，暴露于IL-12后会上调T-bet和干扰素-γ（IFN-γ）的表达。虽然T-bet对于TGM细胞的发育不是必需的，但对于其致脑炎性至关重要。这些发现表明，TGM细胞构成了一个具有谱系特征的独特T细胞群体，易于呈现T1表型并促进神经炎症。
