TNF-α drives human CD14+ monocytes to differentiate into CD70+ dendritic cells evoking Th1 and Th17 responses
TNF-α drives human CD14+ monocytes to differentiate into CD70+ dendritic cells evoking Th1 and Th17 responses
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DOI：
10.4049/jimmunol.179.3.1449
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发表时间：
2007-08-01
影响因子：
4.4
通讯作者：
Miyazaki, Akira
中科院分区：
文献类型：
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作者：
Iwamoto, Sanju;Iwai, Shin-ichi;Miyazaki, Akira
许多涉及肿瘤坏死因子 -α（TNF -α）、1型辅助性T细胞（Th1）应答和17型辅助性T细胞（Th17）应答的机制与慢性炎症性自身免疫疾病有关。最近，抗TNF疗法对疾病进展的临床影响促使人们对这种细胞因子的核心作用进行重新评估，并产生了TNF依赖性免疫的新概念。然而，TNF -α与发病机制的整体关系尚不清楚。在此，我们展示了一种树突状细胞（DC）的TNF依赖性分化途径，该途径可引发Th1和Th17应答。在TNF -α和粒细胞 - 巨噬细胞集落刺激因子（GM - CSF）存在的情况下培养的CD14⁺单核细胞转化为CD14⁺CD1a低表达的贴壁细胞，其刺激T细胞的能力较弱。然而，在脂多糖（LPS）刺激下，它们会产生高水平的TNF -α、基质金属蛋白酶（MMP）- 9和白细胞介素 - 23，并分化为成熟的DC或活化的巨噬细胞（Mφ）。成熟的DC（CD83⁺CD70⁺HLA - DR高表达CD14低表达）表达高水平的白细胞介素 - 6、白细胞介素 - 15和白细胞介素 - 23的信使核糖核酸（mRNA），诱导初始CD4⁺T细胞产生干扰素 -γ和TNF -α，并刺激静息的CD4⁺T细胞分泌白细胞介素 - 17。有趣的是，添加到单核细胞培养基中的TNF -α决定了LPS诱导的成熟程度以及所衍生DC的功能。相比之下，Mφ（CD14高表达CD70⁺CD83⁻HLA - DR⁻）在没有外源性TNF刺激的情况下产生大量的MMP - 9和TNF -α。这些结果表明，单核细胞的TNF启动控制由成熟DC诱导的Th1和Th17应答，但不控制由活化的Mφ诱导的炎症。因此，用TNF -α对单核细胞进行额外刺激可能会促进TNF依赖性适应性免疫以及GM - CSF刺激的Mφ介导的先天性免疫。
Many mechanisms involving TNF-alpha, Th1 responses, and Th17 responses are implicated in chronic inflammatory autoimmune disease. Recently, the clinical impact of anti-TNF therapy on disease progression has resulted in re-evaluation of the central role of this cytokine and engendered novel concept of TNF-dependent immunity. However, the overall relationship of TNF-a to pathogenesis is unclear. Here, we demonstrate a TNF-dependent differentiation pathway of dendritic cells (DC) evoking Th1 and Th17 responses. CD14(+) monocytes cultured in the presence of TNF-a and GM-CSF converted to CD14(+) CDla(low) adherent cells with little capacity to stimulate T cells. On stimulation by LPS, however, they produced high levels of TNF-a, matrix metalloproteinase (MMP)-9, and IL-23 and differentiated either into mature DC or activated macrophages (M phi). The mature DC (CD83(+) CD70(+) HLA-DRhigh CD14(low)) expressed high levels of mRNA for IL-6, IL-15, and IL-23, induced naive CD4 T cells to produce IFN-gamma and TNF-alpha, and stimulated resting CD4 T cells to secret IL-17. Intriguingly, TNF-alpha added to the monocyte culture medium determined the magnitude of LPS-induced maturation and the functions of the derived DC. In contrast, the M phi (CD14(high) CD70(+)CD83(-)HLA-DR-) produced large amounts of MMP-9 and TNF-alpha without exogenous TNF stimulation. These results suggest that the TNF priming of monocytes controls Th1 and Th17 responses induced by mature DC, but not inflammation induced by activated M h. Therefore, additional stimulation of monocytes with TNF-a may facilitate TNF-dependent adaptive immunity together with GM-CSF-stimulated M phi-mediated innate immunity.