Soluble TNF-α but not transmembrane TNF-α sensitizes T cells for enhanced activation-induced cell death
Soluble TNF-α but not transmembrane TNF-α sensitizes T cells for enhanced activation-induced cell death
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DOI：
10.1002/eji.200939554
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发表时间：
2009-11-01
影响因子：
5.4
通讯作者：
Mueller, Christoph
中科院分区：
文献类型：
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作者：
Mueller, Stefan;Rihs, Silvia;Mueller, Christoph
除了促炎作用外，肿瘤坏死因子-α还表现出免疫抑制作用。在这里，我们比较了跨膜型肿瘤坏死因子-α(TmTNF)和可溶性肿瘤坏死因子-α(STNF)在调节活化的T细胞通过凋亡而扩张方面的能力。表达不可切割突变体tmTNF的wtTNF、肿瘤坏死因子α缺陷型(-/-)和肿瘤坏死因子(-/-)小鼠的脾CD4(+)T细胞在TCR介导的刺激下表现出相似的增殖率。然而，与wtTNFCD4(+)T细胞相比，tmTNF4(-/-)T细胞的活化诱导细胞死亡(AICD)显著减轻。在初始预刺激时加入sTNF足以增强tmTNF和肿瘤坏死因子(-/-)CD4(+)T细胞对AICD的易感性，达到wtTFCD4(+)T细胞的水平，而仅在再刺激期间加入sTNF则不能增强AICD。STNF诱导的AICD敏感性增强依赖于这两种肿瘤坏死因子受体。在过继转移的CD4(+)T细胞介导的结肠炎的体内模型中，tmTNF CD4(+)T细胞对AICD的敏感性降低也是明显的。因此，在T细胞启动过程中，sTNF的存在可能是一个重要的机制，使激活的T细胞对凋亡敏感，从而减轻T细胞反应的程度和持续时间，以及随后T细胞介导的过度炎症。
in addition to its proinflammatory effects, TNF-alpha exhibits immunosuppression. Here, we compared the capacities of transmembrane TNF-alpha (tmTNF) and soluble TNF-alpha (sTNF) in regulating expansion of activated T cells by apoptosis. Splenic CD4(+) T cells from wtTNF, TNF-alpha-deficient (TNF(-/-)) and TNF(-/-) mice expressing a non-cleavable mutant tmTNF showed comparable proliferation rates upon TCR-mediated stimulation. Activation-induced cell death (AICD), however, was significantly attenuated in tmTNF and TNF(-/-), compared with wtTNF CD4(+) T cells. Addition of sTNF during initial priming was sufficient to enhance susceptibility to AICD in tmTNF and TNF(-/-) CD4(+) T cells to levels seen in wtTNF CD4(+) T cells, whereas addition of sTNF only during restimulation failed to enhance AICD. sTNF-induced, enhanced susceptibility to AICD was dependent on both TNF receptors. The reduced susceptibility of tmTNF CD4(+) T cells for AICD was also evident in an in vivo model of adoptively transferred CD4(+) T-cell-mediated colonic inflammation. Hence, the presence of sTNF during T-cell priming may represent an important mechanism to sensitize activated T cells for apoptosis, thereby attenuating the extent and duration of T-cell reactivities and subsequent T-cell-mediated, excessive inflammation.