Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen

By A. Doedens, Anthony T. Phan, Martin H. Stradner, Jessica K Fujimoto, Jessica V. Nguyen, E. Yang, Richard J. Johnson, Ananda W. Goldrath. Nature Immunology, 2013

603 citations recorded by the source corpus.

Cytolytic activity by CD8+ cytotoxic T lymphocytes (CTLs) is a powerful strategy for the elimination of intracellular pathogens and tumor cells. The destructive capacity of CTLs is progressively dampened during chronic infection, yet the environmental cues and molecular pathways that influence immunological 'exhaustion' remain unclear. Here we found that CTL immunity was regulated by the central transcriptional response to hypoxia, which is controlled in part by hypoxia-inducible factors (HIFs) and the von Hippel–Lindau tumor suppressor VHL. Loss of VHL, the main negative regulator of HIFs, led to lethal CTL-mediated immunopathology during chronic infection, and VHL-deficient CTLs displayed enhanced control of persistent viral infection and neoplastic growth. We found that HIFs and oxygen influenced the expression of pivotal transcription, effector and costimulatory-inhibitory molecules of CTLs, which was relevant to strategies that promote the clearance of viruses and tumors.

Subfields: Cancer Research, Immunology

View Paper: https://www.semanticscholar.org/paper/6b30bb79507692349897bbbcfde14c8d59b676e1

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Citations in the corpus

Unraveling the Complex Interplay Between T Cell Metabolism and Function (2018, background): “Illustrating how glycolysis is tightly linked to T cell function, mice with sustained activation of the glycolysis activator hypoxia-inducible factor 1 alpha (Hif-1α) in T cells exhibit better tumor control in a cancer model compared to control mice, but they also succumb to ongoing inflammation dur”
T Cell Dysfunction in Cancer (2018, background): “On the other hand, hypoxia induces increased expression and activity of the transcription factor hypoxiainducible factor 1α (HIF-1α), which promotes the expression of inhibitory receptors on T cells (Doedens et al., 2013), and leads to a reduction in T cell effector functions (Fischer et al., 2007).”
T cell metabolism drives immunity (2015, background): “Deletion of its negative regulator, von Hippel-Lindau (VHL), enhances HIF-1–mediated CD8 T cell glycolysis and effector responses to persistent viral infection (Doedens et al., 2013).”
Metabolic Instruction of Immunity (2017, positive): “…adapt to metabolic perturbations in the tumor microenvironment may be another viable strategy to improve antitumor immunity (Clever et al., 2016; Doedens et al., 2013; Ho et al., 2015; Scharping et al., 2016), especially for adoptive cell therapy, a personalized form of cancer treatment that…”
Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses (2015, background): “Additionally, rewiring the metabolic activity of TILs, as demonstrated herein and elsewhere (Doedens et al., 2013), could pose a new strategy for enhancing the potency and durability of ACT.”