Immune memory-boosting dose of rapamycin impairs macrophage vesicle acidification and curtails glycolysis in effector CD8 cells, impairing defense against acute infections.
Immune memory-boosting dose of rapamycin impairs macrophage vesicle acidification and curtails glycolysis in effector CD8 cells, impairing defense against acute infections.
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DOI：
10.4049/jimmunol.1400188
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发表时间：
2014-07-15
期刊：
影响因子：
--
通讯作者：
Nikolich-Žugich J
中科院分区：
文献类型：
--
作者：
Goldberg EL;Smithey MJ;Lutes LK;Uhrlaub JL;Nikolich-Žugich J
最近研究表明，短期小剂量雷帕霉素直接抑制mTORC1可以改善CD8T细胞的免疫记忆。虽然这些研究侧重于记忆发育，但低剂量雷帕霉素对初级免疫反应的影响，特别是与功能效应器免疫有关的影响，远不清楚。我们研究了急性雷帕霉素治疗对几种急性感染的初次免疫应答中免疫效应细胞功能的影响。我们发现，在小鼠体内和在体外，面对低剂量雷帕霉素治疗，功能性CD8 T细胞和巨噬细胞对病毒和细胞内细菌病原体的反应受到抑制，对佛波酯和钙离子载体的刺激。从机制上讲，CD8缺陷与受刺激的幼稚细胞糖酵解开关受损和短期效应细胞(SLEC)的形成减少有关。因此，在小鼠和人类中，保护性效应器免疫反应所需的不止一种细胞类型受到雷帕霉素的损害，剂量为改善免疫记忆和延长寿命。这敦促人们对雷帕霉素治疗作为改善免疫记忆手段的相对治疗成本和好处持谨慎态度。
Direct mTORC1 inhibition by short-term low-dose rapamycin treatment has recently been shown to improve CD8 T cell immunological memory. While these studies focused on memory development, the impact of low-dose rapamycin on the primary immune response, particularly as it relates to functional effector immunity, is far less clear. We investigated the impact of acute rapamycin treatment on immune effector cell function during the primary immune response to several acute infections. We found that functional CD8 T cell and macrophage responses to both viral and intracellular bacterial pathogens were depressed in mice in vivo and in humans to phorbol ester and calcium ionophore stimulation in vitro in the face of low-dose rapamycin treatment. Mechanistically, the CD8 defect was linked to impaired glycolytic switch in stimulated naïve cells and the reduced formation of short-lived effector cells (SLEC). Therefore, more than one cell type required for a protective effector immune response are impaired by rapamycin in both mice and humans, at the dose shown to improve immune memory and extend lifespan. This urges caution with regard to the relative therapeutic costs and benefits of rapamycin treatment as means to improve immune memory.
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影响因子：
16.8
作者：
Gerriets VA;Rathmell JC
通讯作者：
Rathmell JC
DOI：
10.1038/nri2888
发表时间：
2011-02
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1186/1742-4933-9-17
发表时间：
2012-08-15
期刊：
Immunity & ageing : I & A
影响因子：
--
作者：
Bunztman A;Vincent BG;Krovi H;Steele S;Frelinger JA
通讯作者：
Frelinger JA
影响因子：
64.5
作者：
Chang CH;Curtis JD;Maggi LB Jr;Faubert B;Villarino AV;O'Sullivan D;Huang SC;van der Windt GJ;Blagih J;Qiu J;Weber JD;Pearce EJ;Jones RG;Pearce EL
通讯作者：
Pearce EL
影响因子：
64.8
作者：
Cunningham, John T.;Rodgers, Joseph T.;Puigserver, Pere
通讯作者：
Puigserver, Pere