Control of TH17/Treg Balance by Hypoxia-Inducible Factor 1

Abstract

SUMMARY T cell differentiation into distinct functional effector and inhibitory subsets is regulated in part by the cytokine environment present at the time of antigen recognition. Here, we show that hypoxia-inducible factor 1 (HIF-1), a key metabolic sensor, regulates the balance between T regulatory (Treg) and TH17 differentiation. HIF-1α enhances TH17 development through direct transcriptional activation of RORvt, and via tertiary complex formation with RORvt and p300 recruitment to the IL17 promoter, thereby regulating TH17 signature genes. Concurrently, HIF-1α attenuates Treg development by binding Foxp3 and targeting it for proteasomal degradation. Importantly this regulation occurs under both normoxic and hypoxic conditions. Mice with HIF-1α deficient T cells are resistant to induction of TH17-dependent experimental autoimmune encephalitis associated with diminished TH17 and increased Treg cells. These findings highlight the importance of metabolic cues in T cell fate determination and suggest that metabolic modulation could ameliorate certain T cell-based immune pathologies.

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

“…Indeed, deletion in T Reg cells of von Hippel-Lindau (VHL), an E3 ubiquitin ligase that targets HIF1α, increases HIF1α activity, leading to ectopic IFNγ production and reduced FOXP3 expression 103 . HIF1α has a particularly important role in T H 17 cell polarization, for which, in addition to promoting glycolysis, it directly induces the expression of RORγt and supports its function 102,104 . The transcriptional activity of HIF1α is also opposed by the transcriptional repressor BCL-6 (B cell lymphoma 6), which competes for binding to many of the same genes, preventing the induction of glycolytic genes that may be detrimental to the T FH cell programme 105 .…”

Succinate: a metabolic signal in inflammation

“…Indeed, the metabolic sensor HIF-1a can determine the growth and fate of both tumor cells and immune cells. For example, HIF-1a activation favors differentiation of T lymphocytes into proinflammatory Th17 cells and attenuates regulatory T cell development [7]. Importantly, as well as global changes in metabolism that occur in activated immune cells, individual metabolites, including succinate, citrate, and NAD + , have been demonstrated to possess signaling capacity and to influence immunity [4,8,9].…”

“…It is elevated in macrophages in the inflamed synovium in rheumatoid arthritis [25], and this may be important for the induction of IL-1b involved in synovial inflammation. HIF-1a enhances differentiation of T lymphocytes into the proinflammatory Th17 subtype [7] by inducing IL-17 production and by enhancing the transcription of RAR-related orphan receptor gt (RORgt), the key transcription factor required for Th17 cell development. Whether succinate is needed for the Th17 response has yet to be determined.…”

Disease tolerance and immunity in host protection against infection

“…How these apparently conflicting activities exerted by cytokines such as TNF or ROS are resolved remains to be understood 23 activation in macrophages 36 and T cells 92 exerts immunoregulatory effects that promote tissue damage control. Furthermore, HIF1α orchestrates a metabolic response in macrophages 40,93 and shifts the balance between T H 17 and T REG cells 94 , modulating immune-driven resistance and possibly disease tolerance to infection. Activation of other stress and damage responses in tissue resident leukocytes is likely to exert similar effects, but this is yet to be determined experimentally.…”