Department of Neurology, Thomas Jefferson University, Philadelphia, PA, United States.
Sidney Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, United States.
Front Immunol. 2022 Jul 4;13:912583. doi: 10.3389/fimmu.2022.912583. eCollection 2022.
GM-CSF-producing T helper (Th) cells play a crucial role in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). Recent studies have identified a distinct population of GM-CSF-producing Th cells, named ThGM cells, that also express cytokines TNF, IL-2, and IL-3, but lack expression of master transcription factors (TF) and signature cytokines of commonly recognized Th cell lineages. ThGM cells are highly encephalitogenic in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Similar to Th17 cells, in response to IL-12, ThGM cells upregulate expression of T-bet and IFN-γ and switch their phenotype to Th1. Here we show that in addition to T-bet, TF RUNX3 also contributes to the Th1 switch of ThGM cells. T-bet-deficient ThGM cells in the CNS of mice with EAE had low expression of RUNX3, and knockdown of RUNX3 expression in ThGM cells abrogated the Th1-inducing effect of IL-12. Comparison of ThGM and Th1 cell transcriptomes showed that ThGM cells expressed a set of TFs known to inhibit the development of other Th lineages. Lack of expression of lineage-specific cytokines and TFs by ThGM cells, together with expression of TFs that inhibit the development of other Th lineages, suggests that ThGM cells are a non-polarized subset of Th cells with lineage characteristics.
产生粒细胞-巨噬细胞集落刺激因子的辅助性 T 细胞（Th）在多发性硬化症（MS）等自身免疫性疾病的发病机制中发挥着关键作用。最近的研究确定了一种独特的产生粒细胞-巨噬细胞集落刺激因子的 Th 细胞群，称为 ThGM 细胞，这些细胞还表达 TNF、IL-2 和 IL-3 细胞因子，但缺乏通常识别的 Th 细胞谱系的主转录因子（TF）和特征性细胞因子的表达。在 MS 的小鼠模型实验性自身免疫性脑脊髓炎（EAE）中，ThGM 细胞具有高度的致脑炎作用。与 Th17 细胞类似，在 IL-12 的作用下，ThGM 细胞上调 T-bet 和 IFN-γ 的表达，并将其表型转换为 Th1。在这里，我们表明除了 T-bet 之外，TF RUNX3 也有助于 ThGM 细胞的 Th1 转换。EAE 小鼠中枢神经系统中的 T-bet 缺陷型 ThGM 细胞中 RUNX3 的表达较低，而 ThGM 细胞中 RUNX3 表达的敲低则消除了 IL-12 的 Th1 诱导作用。对 ThGM 和 Th1 细胞转录组的比较表明，ThGM 细胞表达了一组已知抑制其他 Th 谱系发育的 TF。ThGM 细胞缺乏谱系特异性细胞因子和 TF 的表达，以及抑制其他 Th 谱系发育的 TF 的表达，表明 ThGM 细胞是具有谱系特征的非极化 Th 细胞亚群。
