TNF plays a crucial role in inflammation by signaling via T cell TNFR2
TNF plays a crucial role in inflammation by signaling via T cell TNFR2
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DOI：
10.1073/pnas.2109972118
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发表时间：
2021-12-14
影响因子：
11.1
通讯作者：
Ashwell, Jonathan D.
中科院分区：
文献类型：
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作者：
Alam, Muhammad S.;Otsuka, Shizuka;Ashwell, Jonathan D.
主要由T细胞和先天免疫细胞产生的TNF具有强效促炎作用，Th 1和Th 17细胞分别产生的细胞因子（例如IFN-γ和IL-17）也是如此。在这里，我们问，如果TNF是上游Th偏向炎症表型。将小鼠CD 4（+）T细胞暴露于TNF和TGF-β产生Th 17细胞，其表达低水平的IL-17（ROR-γ t（+）IL-17（lo））和高水平的独立于IL-6和STAT 3的炎性标志物。这是由非死亡TNF受体TNFR 2介导的，TNFR 2也有助于炎症性Th 1细胞的产生。小鼠实验性自身免疫性脑脊髓炎（EAE）中中枢神经系统浸润性CD 4（+）T细胞的单细胞RNA测序发现，炎症基因表达谱与多发性硬化患者脑脊液浸润性CD 4（+）T细胞相似。值得注意的是，TNFR 2缺陷型CD 4（+）T细胞产生较少的炎症介质，在EAE和结肠炎中的致病性较低。IL-1 β，一种Th 17-偏斜细胞因子，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），其通过TNFR 2信号传导的破坏而被抑制，证明IL-1 β可以通过TNF的产生间接地起作用。因此，TNF不仅是炎症Th分化的效应子，而且是炎症Th分化的启动子。
TNF, produced largely by T and innate immune cells, is potently proinflammatory, as are cytokines such as IFN-gamma 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-beta generated Th17 cells that express low levels of IL-17 (ROR-gamma t(+)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-1 beta, 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-1 beta can function indirectly via the production of TNF. Thus, TNF is not just an effector but also an initiator of inflammatory Th differentiation.