TNF Activates a NF-κB-Regulated Cellular Program in Human CD45RA- Regulatory T Cells that Modulates Their Suppressive Function
TNF Activates a NF-κB-Regulated Cellular Program in Human CD45RA- Regulatory T Cells that Modulates Their Suppressive Function
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DOI：
10.4049/jimmunol.0902070
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发表时间：
2010-04-01
影响因子：
4.4
通讯作者：
Goldstein, Itamar
中科院分区：
文献类型：
--
作者：
Nagar, Meital;Jacob-Hirsch, Jasmine;Goldstein, Itamar
新出现的数据表明，调节性T细胞（Treg）功能障碍和随之而来的自身免疫中免疫自身耐受性的破坏可以由非Treg内在的因子（例如，细胞因子）。事实上，最近的研究表明，在类风湿性关节炎中，促炎细胞因子TNF降低了TGFAP的抑制功能，而体内TNF阻断恢复了该功能并因此恢复了自身耐受性。然而，到目前为止，还没有描述TNF调节Treg的相关机制。在这篇文章中，我们发现，与CD 25（-）常规T细胞相比，TNF诱导人T细胞中经典NF-κ B通路的优先和显著活化。此外，TNF主要在高度富集典型NF-κ B B靶基因的CD 45 RA（-）TcA转录程序中诱导，所述靶基因例如细胞因子α-光敏素-α和TNF、TNFR超家族成员FAS、4-伊布和OX-40、各种抗凋亡基因和其它重要的免疫应答基因。流式细胞仪分析显示TNF还诱导细胞表面4-1BB和OX 40的表达上调，特异性地在CD 45 RA（-）FOXP 3（+）TcB中。相比之下，TNF对Treg的核心转录特征或对TcB中FOXP 3蛋白的细胞内水平仅具有最小的影响。重要的是，TNF治疗调节了TGFAP抑制常规T细胞增殖和IFN-γ分泌的能力，这种作用可通过与抗TNFR 2 mAb共治疗完全逆转。因此，我们的研究结果提供了新的机制洞察TNF和TNFR 2在自身免疫发病机制中的作用。免疫学杂志，2010，184：3570-3581。
Emerging data suggest that regulatory T cell (Treg) dysfunction and consequent breakdown of immunological self-tolerance in autoimmunity can be mediated by factors that are not Treg-intrinsic (e.g., cytokines). Indeed, recent studies show that in rheumatoid arthritis the proinflammatory cytokine TNF reduces the suppressive function of Tregs, whereas in vivo TNF blockade restores this function and accordingly self-tolerance. However, until now a coherent mechanism by which TNF regulates the Treg has not been described. In this paper, we show that TNF induces preferential and significant activation of the canonical NF-kappa B pathway in human Tregs as compared with CD25(-) conventional T cells. Furthermore, TNF induced primarily in CD45RA(-) Tregs a transcription program highly enriched for typical NF-kappa B target genes, such as the cytokines lymphotoxin-alpha and TNF, the TNFR superfamily members FAS, 4-IBB, and OX-40, various antiapoptotic genes, and other important immune-response genes. FACS analysis revealed that TNF also induced upregulation of cell surface expression of 4-1BB and OX40 specifically in CD45RA(-)FOXP3(+) Tregs. In contrast, TNF had only a minimal effect on the Treg's core transcriptional signature or on the intracellular levels of the FOXP3 protein in Tregs. Importantly, TNF treatment modulated the capacity of Tregs to suppress the proliferation and IFN-gamma secretion by conventional T cells, an effect that was fully reversed by cotreatment with anti-TNFR2 mAbs. Our findings thus provide new mechanistic insight into the role of TNF and TNFR2 in the pathogenesis of autoimmunity. The Journal of Immunology, 2010, 184: 3570-3581.