Interleukin 21 up-regulates perforin-mediated cytotoxic activity of human intra-epithelial lymphocytes
Interleukin 21 up-regulates perforin-mediated cytotoxic activity of human intra-epithelial lymphocytes
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DOI：
10.1111/j.1365-2567.2008.02941.x
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发表时间：
2009-06-01
期刊：
影响因子：
6.4
通讯作者：
Ebert, Ellen C.
中科院分区：
文献类型：
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作者：
Ebert, Ellen C.
人上皮内淋巴细胞(IEL)主要是位于肠上皮细胞之间的T细胞受体-αβ(+)(TCR-αβ(+))、CD8(+)、CD45RO(+)记忆T细胞。它们对白介素15刺激的反应程度大于对CD3/TCR触发的反应，这表明它们对当地环境中的细胞因子环境而不是对同源抗原做出反应。一种新发现的伽马C细胞因子家族成员IL-21具有很强的抗肿瘤作用。由于IEL类似于浸润性肿瘤性病变的淋巴细胞，它们对IL-21的反应可能与体内相关。在这里，IL-21被证明增加穿孔素介导的细胞毒性和IELs释放的丝氨酸酯酶。这种IL-21介导的上调发生在IEL存活或细胞分裂没有改变的情况下。有趣的是，IL-21的作用没有增加信号转导和转录激活因子(STAT)1、STAT3、STAT4、STAT5、细胞外信号调节激酶(ERK)或p38的磷酸化。IL-21对Fas配体(FL)或肿瘤坏死因子-α(TNF-α)介导的细胞毒作用无影响，但可下调IL-15刺激的CD25和CD94的表达，表明其既有积极作用，也有消极作用。这种功能是人类IEL所独有的，强调它们是淋巴细胞的一个不同的隔室，IL-21可能促进它们在肿瘤免疫监控中的作用。
Human intra-epithelial lymphocytes (IELs) are predominantly T-cell receptor-alpha beta(+) (TCR-alpha beta(+)) CD8(+) CD45RO(+) memory T cells located between intestinal epithelial cells. They respond to a greater extent to stimulation with interleukin (IL)-15 than to CD3/TCR triggering, suggesting that they react to the cytokine milieu in their local environment rather than to cognate antigen. A newly described member of the gamma c cytokine family, IL-21, has potent antitumor effects. As IELs resemble lymphocytes infiltrating neoplastic lesions, their response to IL-21 may be relevant in vivo. Here, IL-21 was shown to increase perforin-mediated cytotoxicity and serine esterase release by IELs. This IL-21-mediated up-regulation occurred without changes in IEL survival or cell division. Interestingly, the effects of IL-21 occurred without increased phosphorylation of signal transducer and activator of transcription (STAT) 1, STAT3, STAT4, STAT5, extracellular signal-regulated kinase (ERK), or p38. IL-21 had no effect on Fas ligand (FL)- or tumour necrosis factor-alpha (TNF-alpha)-mediated cytotoxicity, but it down-regulated IL-15-stimulated expression of CD25 and CD94, indicating that it has both positive and negative actions. This functional profile is unique to human IELs, emphasizing that they are a distinct compartment of lymphocytes and that IL-21 may promote their role in tumour immunosurveillance.