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

Abstract

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 up-regulation of mitochondrial pathways, which was consistent with increased mass and metabolism 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 mouse model conferred enhanced therapeutic efficacy, raising the possibility that exposure of T cells to febrile temperatures could have clinical potential.

Targeting memory T cell metabolism to improve immunity

“…The first approach embraces in vitro preconditioning of cells with metabolic modulators before adoptive transfer. Examples include inhibiting Akt function to favor a more Tm cell–like metabolic phenotype in mouse melanoma models ( 59 ); using sodium bicarbonate to reverse the lactic acid–induced interference with T cell glycolysis and cytotoxic function in mouse models and patients with acute myeloid leukemia ( 110 ); and transiently exposing donor lymphocytes to 39°C prior to infusion in a myeloid leukemia mouse model ( 158 ). Similarly, preconditioning T cells with IL-15, which drives Tm cell differentiation and metabolically increases spare respiratory capacity ( 66 ), has similar positive results in HER2-positive tumors, leukemia, and glioma models ( 159 – 161 ).…”

Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating T cells

“…Specifically, we discovered a loss of KLF and ETS:RUNX activity in T EX , while an intense heat shock signature was dominating both cytotoxic and dysfunctional TILs, suggesting that heat shock responses exert additive chromatin remodelling to other T cell states. In light of the sustained positive effect of heat 50 on tumor control by T cells this observation merits further investigation of the underlying molecular mechanisms of heat shock proteins on T cell gene-regulatory cues. Further, our analysis suggests an involvement of different nuclear receptors and octamer transcription factors in shaping T cell dysfunction in the tumor.…”

Heat Treatment Promotes Ubiquitin-Mediated Proteolysis of SARS-CoV-2 RNA Polymerase and Decreases Viral Load

“…Notably, daily mild heat treatment (40°C, 0.5 h/day) is sufficient to maintain low levels of both WT and P323L mutant of NSP12 (Figures 1(n) and 1(o) , compare lanes 3, 4 to 1), suggesting clinical potential of heat treatment against both WT and P323L mutation harboring SARS-CoV-2 variants. In addition, it is demonstrated that mild heat treatment upregulates the immune function [ 16 , 17 ], which might contribute to inhibition of SARS-CoV-2 fitness as well. Comorbidities such as chronic diseases and acute organ injuries are strongly correlated with disease severity and mortality among COVID-19 patients [ 18 ].…”