TNF, produced largely by T and innate immune cells, is potently proinflammatory, as are cytokines such as IFN-γ and IL-17 produced by Th1 and Th17 cells, respectively. Here, we asked if TNF is upstream of Th skewing toward inflammatory phenotypes. Exposure of mouse CD4⁺ T cells to TNF and TGF-β generated Th17 cells that express low levels of IL-17 (ROR-γt⁺IL-17^lo) and high levels of inflammatory markers independently of IL-6 and STAT3. This was mediated by the nondeath TNF receptor TNFR2, which also contributed to the generation of inflammatory Th1 cells. Single-cell RNA sequencing of central nervous system–infiltrating CD4⁺ T cells in mouse experimental autoimmune encephalomyelitis (EAE) found an inflammatory gene expression profile similar to cerebrospinal fluid–infiltrating CD4⁺ T cells from patients with multiple sclerosis. Notably, TNFR2-deficient CD4⁺ T cells produced fewer inflammatory mediators and were less pathogenic in EAE and colitis. IL-1β, a Th17-skewing cytokine, induced TNF and proinflammatory granulocyte-macrophage colony-stimulating factor (GM-CSF) in T cells, which was inhibited by disruption of TNFR2 signaling, demonstrating IL-1β can function indirectly via the production of TNF. Thus, TNF is not just an effector but also an initiator of inflammatory Th differentiation.

TNF 主要由 T 细胞和先天免疫细胞产生，具有强效促炎作用，细胞因子如 Th1 和 Th17 细胞分别产生的 IFN-γ 和 IL-17 也是如此。在这里，我们询问 TNF 是否位于 Th 的上游，倾向于炎症表型。^{小鼠 CD4 +} T 细胞暴露于 TNF 和 TGF-β 产生的 Th17 细胞表达低水平的 IL-17 (ROR-γt ⁺ IL-17 ^lo ) 和独立于 IL-6 和 STAT3 的高水平炎症标志物。这是由非死亡 TNF 受体 TNFR2 介导的，这也有助于炎症 Th1 细胞的产生。中枢神经系统单细胞 RNA 测序——浸润 CD4 ⁺小鼠实验性自身免疫性脑脊髓炎 (EAE) 中的 T 细胞发现炎症基因表达谱类似于来自多发性硬化症患者的脑脊液浸润 CD4 ^{+ T 细胞。}值得注意的是，缺乏 TNFR2 的 CD4 ⁺ T 细胞产生较少的炎症介质，并且在 EAE 和结肠炎中的致病性较低。IL-1β 是一种 Th17 偏斜细胞因子，可在 T 细胞中诱导 TNF 和促炎性粒细胞 - 巨噬细胞集落刺激因子 (GM-CSF)，其被 TNFR2 信号传导的破坏所抑制，这表明 IL-1β 可以通过产生肿瘤坏死因子。因此，TNF 不仅是一种效应物，而且是炎症性 Th 分化的引发剂。