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

Abstract

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.

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

“…In strong support of this concept, it was recently shown that a high dose virus infection, which induced a strong "exhausted" phenotype, protected mice from immunopathology while a lower dose, which failed to induce an "exhausted" phenotype, resulted in substantial pathology 74,77 . Similarly, disrupting the von Hippel-Lindau tumor suppressor (VHL) gene causes overwhelming immunopathology by enforcing cytotoxic activity of T-cells in persisting infections 78 .…”

Proteasome activity regulates CD8+ T lymphocyte metabolism and fate specification

“…We next sought to determine the mechanism by which proteasome activity influences the glycolytic transcriptional program. Several key transcription factors, including Myc, estrogen-related receptor α (ERRα), and hypoxia-inducible factor 1-α (HIF1α), have been shown to facilitate metabolic reprogramming by upregulating genes associated with the glycolytic pathway (1,(40)(41)(42). Conversely, Bcl-6 directly represses genes encoding the glycolytic pathway, while Foxo1 positively regulates genes involved in mitochondrial function and fatty acid metabolism (43,44).…”

Tsc1 promotes the differentiation of memory CD8 + T cells via orchestrating the transcriptional and metabolic programs

“…For instance, the increased glycolytic metabolism promotes effector T-cell generation (11), whereas oxidative phosphorylation and mitochondrial spare respiratory capacity facilitate memory T-cell differentiation (12,13). Recent studies have also identified transcriptional regulators of cell metabolism that promote effector T-cell differentiation, including HIF1 and IRF4 (14)(15)(16)(17). In contrast, how cell metabolism is regulated by immune signaling pathways in effector and memory T-cell differentiation remains unclear.…”