Fever supports CD8+ effector T cell responses by promoting mitochondrial translation

Fever can provide a survival advantage during infection. Metabolic processes are sensitive to environmental conditions, but the effect of fever on T cell metabolism is not well characterized. We show that in activated CD8+ T cells, exposure to febrile temperature (39°C) augmented metabolic activity and T cell effector functions, despite having a limited effect on proliferation or activation marker expression. Transcriptional profiling revealed an upregulation of mitochondrial pathways, which was consistent with increased mitochondrial metabolism and mass observed in T cells exposed to 39°C. Through in vitro and in vivo models we determined that mitochondrial translation is integral to the enhanced metabolic activity and function of CD8+ T cells exposed to febrile temperature. Transiently exposing donor lymphocytes to 39°C prior to infusion in a myeloid leukemia (ML) mouse model conferred enhanced therapeutic efficacy, raising the possibility that exposure of T cells to febrile temperatures could have clinical potential. Naive CD8+ T cells were isolated from spleen and lymph nodes from 6-12 week old micel. Isolated T cells (1x10^6/ml) were activated using plate bound αCD3 (5 μg/ml) and soluble αCD28 (0.5 μg/ml) in T cell media (TCM; 1640 RPMI with 10% fatal calf serum, 4mM L-glutamine, 1% penicillin/streptomycin, 55μM beta-mercaptoethanol) supplemented with 100 U/ml hrIL-2 (Peprotech). Cells were cultured a 37°C or 39°C as indicated in humidified incubators with 5% CO2 and atmospheric oxygen for 24 or 48 hours following activation. RNA was extracted from 3 independent biological replicates in each treatment and then sequenced.

发热可在感染过程中为机体提供生存优势。代谢过程对环境条件极为敏感，但目前对于发热如何影响T细胞代谢的机制尚未得到充分阐明。本研究显示，在活化的CD8+ T细胞中，暴露于发热温度（39°C）可增强其代谢活性与效应功能，尽管该处理对细胞增殖或活化标志物的表达影响有限。转录组测序分析显示，线粒体通路出现显著上调，这与在39°C环境下培养的T细胞中观察到的线粒体代谢增强及线粒体质量增加的结果一致。通过体外与体内模型，我们证实线粒体翻译对于发热温度下CD8+ T细胞代谢活性与功能的增强是不可或缺的。在髓系白血病（myeloid leukemia, ML）小鼠模型中，于细胞输注前将供体淋巴细胞短暂暴露于39°C环境，可显著提升其治疗功效，这提示将T细胞暴露于发热温度或具有潜在临床应用价值。我们从6至12周龄小鼠的脾脏与淋巴结中分离初始CD8+ T细胞。将分离得到的T细胞（1×10^6/ml）置于T细胞培养基（TCM；含10%胎牛血清、4mM L-谷氨酰胺、1%青霉素/链霉素、55μM β-巯基乙醇的RPMI 1640培养基）中，使用固相包被αCD3（5 μg/ml）与可溶性αCD28（0.5 μg/ml）进行活化，并补充100 U/ml的重组人IL-2（hrIL-2，Peprotech公司）。将活化后的细胞置于含5% CO₂、常压氧气的湿润培养箱中，分别于37°C或39°C条件下培养24小时或48小时，具体时长依照实验设计而定。每组处理设置3次独立生物学重复，提取总RNA后进行测序。