Profound enhancement of the IL-12/IL-18 pathway of IFN-γ secretion in human CD8+ memory T cell subsets via IL-15
Profound enhancement of the IL-12/IL-18 pathway of IFN-γ secretion in human CD8+ memory T cell subsets via IL-15
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DOI：
10.4049/jimmunol.178.8.4786
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发表时间：
2007-04-15
影响因子：
4.4
通讯作者：
Smeltz, Ronald B.
中科院分区：
文献类型：
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作者：
Smeltz, Ronald B.
人类记忆CD8(+)T细胞亚群，称为中枢记忆T细胞和效应记忆T细胞，可通过CD45RA、CD62配体(CD62L)和CCR7的表达来识别。因此，已经描述了每个亚群的功能差异，反映了在免疫记忆中的独特作用。常见的伽玛链细胞因子IL-15和IL-7可诱导人CD8(+)T细胞亚群的增殖和分化，以及增强效应功能(即细胞因子和细胞毒性)。在这项研究中，我们观察到在培养的人CD8(+)T细胞中加入IL-15或IL-7可以显著增强IL-12-IL-18产生干扰素-γ的途径。重要的是，IL-15和IL-7将诱导干扰素-γ所需的IL-12和IL-18的阈值浓度降低了100倍。IL-15和IL-7的比较表明，IL-15增强IL-12-IL-18诱导的干扰素-γ的能力优于IL-15，但没有证据表明IL-15和IL-7之间有协同作用。我们还观察到，IL-15和IL-7介导的增强IL-12-IL-18诱导的干扰素-γ的产生是效应记忆CD8(+)T细胞的一种功能特性。尽管细胞分裂与IL-12-IL-18诱导的干扰素-γ的获得之间缺乏联系，但CD62L表达的下调与IL-12-IL-18诱导的干扰素-γ的升高有很好的相关性。纯化的中枢记忆T细胞在IL-15和IL-7刺激下下调CD62L，并获得与效应性记忆T细胞类似的IL-12-IL-18诱导的干扰素-γ。因此，除了在T细胞记忆发育中的已知作用外，IL-15还可能通过增加对促炎细胞因子刺激的敏感性来放大记忆CD8(+)T细胞效应器的功能。
Human memory CD8(+) T cell subsets, termed central memory and effector memory T cells, can be identified by expression of CD45RA, CD62 ligand (CD62L), and CCR7. Accordingly, functional differences have been described for each subset, reflecting unique roles in immunological memory. The common gamma-chain cytokines IL-15 and IL-7 have been shown to induce proliferation and differentiation of human CD8(+) T cell subsets, as well as increased effector functions (i.e., cytokines, cytotoxicity). In this study, we observed that addition of IL-15 or IL-7 to cultures of human CD8(+) T cells profoundly enhanced the IL-12-IL-18 pathway of IFN-gamma production. Importantly, IL-15 and IL-7 lowered the threshold concentrations of IL-12 and IL-18 required for induction of IFN-gamma by 100-fold. Comparison of IL-15 and IL-7 demonstrated that IL-15 was superior in its ability to enhance IL-12-IL-18-induced IFN-gamma, without evidence of a synergistic effect between IL-15 and IL-7. We also observed that IL-15 and IL-7-mediated enhancement of IL-12-IL-18-induced IFN-gamma production was a functional property of effector memory CD8(+) T cells. Despite a lack of association between cell division and acquisition of IL-12-IL-18-induced IFN-gamma, down-regulation of CD62L expression correlated well with increased IL-12-IL-18-induced IFN-gamma. Purified central memory T cells stimulated with IL-15 and IL-7 down-regulated CD62L and acquired potent IL-12-IL-18-induced IFN-gamma similar to effector memory T cells. Thus, in addition to its known role in development of T cell memory, IL-15 may amplify memory CD8(+) T cell effector functions by increasing sensitivity to proinflammatory cytokine stimulation.