IL-15 Improves Aging-Induced Persistent T Cell Exhaustion in Mouse Models of Repeated Sepsis
IL-15 Improves Aging-Induced Persistent T Cell Exhaustion in Mouse Models of Repeated Sepsis
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DOI：
10.1097/shk.0000000000001352
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发表时间：
2020-02-01
期刊：
影响因子：
3.1
通讯作者：
Kotani, Joji
中科院分区：
文献类型：
--
作者：
Saito, Masafumi;Inoue, Shigeaki;Kotani, Joji
衰老是脓毒症的一个严重问题，而T细胞耗竭是脓毒症诱导的免疫抑制的主要原因。脓毒症和衰老诱导的T细胞耗竭与老年人继发感染的长期预后不良有关。然而，T细胞耗竭的趋势、影响和机制仍不清楚。白细胞介素（IL）-15通过其对T细胞的抗凋亡作用提高脓毒症小鼠的存活率;然而，目前仍不清楚IL-15如何逆转老年脓毒症小鼠中延长的T细胞耗竭。本研究的目的是阐明脓毒症诱导的T细胞衰竭的趋势，以及IL-15是否可以预防脓毒症小鼠中衰老诱导的持续性T细胞衰竭。将保存的盲肠浆液腹膜内注射到年轻小鼠（6周龄）和老年小鼠（18-24月龄）中4次，以诱导临床相关的反复败血症。皮下注射IL-15（1.5 μ g）或磷酸盐缓冲盐水3次，连续测量体重，并连续收集来自其脸颊的外周血细胞50天。老年小鼠脓毒症诱导的T细胞衰竭较青年小鼠严重，同时伴有幼稚CD 4+和CD 8 + T细胞减少（P < 0.01），T细胞表面程序性死亡1表达增加（P <0.01），调节性T细胞数量增加（P < 0.01）。IL-15能显著改善脓毒症所致的T细胞耗竭，增加自然杀伤细胞和巨噬细胞的数量，增强老年脓毒症小鼠的吞噬功能（P < 0.05）。它通过在延长的时间内改善T细胞耗竭来降低与脓毒症幸存者相关的长期死亡率，并且还改善脓毒症小鼠中衰老诱导的持续性T细胞耗竭。
Aging is a grave problem in sepsis, and T cell exhaustion is the main cause of sepsis-induced immunosuppression. Sepsis- and aging-induced T cell exhaustion is related to secondary infection with a poor long-term outcome in the elderly. However, the trend, impact, and mechanism of T cell exhaustion are still unclear. Interleukin (IL)-15 improves survival rate of septic mice via its antiapoptotic effect on T cells; however, it is still unclear how IL-15 reverses prolonged T cell exhaustion in aged septic mice. The purpose of this study was to clarify the trend of sepsis-induced T cell exhaustion and whether IL-15 prevents aging-induced persistent T cell exhaustion in septic mice. Preserved cecal slurry was injected intraperitoneally into young (6-week-old) and aged mice (18-24-month-old) 4 times, to induce clinically relevant repeated sepsis. IL-15 (1.5 mu g) or phosphate-buffered saline was injected subcutaneously 3 times, body weight was serially measured, and peripheral blood cells from their cheek were serially collected for 50 days. Sepsis-induced T cell exhaustion was significantly severe in aged mice than in young mice and was accompanied with decreased naive CD4(+)and CD8(+)T cells (P < 0.01) and increased expression of program death 1 on T cell (P < 0.01) and regulatory T cell population (P < 0.01). IL-15 significantly improved sepsis-induced T exhaustion, with significantly increased numbers of natural killer cells and macrophages, and significantly enhanced phagocytosis activity in aged septic mice (P < 0.05). It decreased the long-term mortality associated with sepsis survivors by improving T cell exhaustion over an extended duration and also ameliorated aging-induced persistent T cell exhaustion in septic mice.