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. Overall design: 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 aCD3 (5 µg/ml) and soluble aCD28 (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.