Polyamine metabolism regulates the T cell epigenome through hypusination

Abstract

We report here a central role for polyamines in T cell differentiation and function. Deficiency in ornithine decarboxylase (ODC), a critical enzyme for polyamine synthesis, resulted in a profound failure of CD4 + T cells to adopt correct subset specification, underscored by ectopic expression of multiple cytokines and lineagedefining transcription factors across T H 1, T H 2, T H 17, and T reg polarizing conditions, and enhanced colitogenic potential. T cells deficient in deoxyhypusine synthase (DHPS) or deoxyhypusine hydroxylase (DOHH), which sequentially utilize polyamines to generate hypusine, phenocopied Odc-deficient T cells, and mice in which T cells lacked Dhps or Dohh developed colitis. Polyamine-hypusine pathway enzyme deficiency caused widespread chromatin and transcriptional dysregulation accompanied by alterations in histone methylation, histone acetylation, and TCA cycle metabolites. Epigenetic modulation by 2-hydroxyglutarate, or histone acetyltransferase inhibition, restored CD4 + T cell subset specification. Thus, polyamine synthesis via hypusine is critical for maintaining the epigenome to focus T H cell subset fidelity.

De novo polyamine synthesis supports metabolic and functional responses in activated murine NK cells

“…Interfering with de novo polyamine synthesis or inhibiting the hypusination of eIF5A was detrimental to NK cell OXPHOS as has been also shown in macrophages [7]. CD4 + T cells lacking either ODC or either enzyme in the hypusination pathway (DHPS or DOHH) had reduced levels of TCA cycle metabolites, suggesting impaired mitochondrial metabolism [6]. Indeed, hypusination of eIF5A is required for the specific translation of certain mitochondrial proteins in macrophages [7].…”

“…Therefore, whether differences in extracellular abundances of polyamines have any effects on NK cells in vivo is an interesting unanswered question. This study in T cells showed that a mechanism linking polyamines to cytokine production involved polyamines impacting upon on epigenetic regulation of the T cells [6]. Interestingly, one outcome of NK cells using the citrate malate shuttle to fuel OXPHOS is the generation of cytosolic acetyl‐CoA that may be important for histone acetylation.…”

“…It is also not clear whether de novo polyamine synthesis may have different effects on NK cell metabolism and function than the addition of exogenously taken up polyamines. Certainly, in activated CD4 + T lymphocytes from ODC −/− mice the addition of exogenous putrescine could rescue dysregulated cytokine production [6]. Therefore, whether differences in extracellular abundances of polyamines have any effects on NK cells in vivo is an interesting unanswered question.…”

“…De novo polyamine synthesis requires the amino acid ornithine, which can be converted into the three polyamines: putrescene, spermidine, and spermine. Recent work has identified the importance of polyamines for other immune cells including macrophages, CD4 + T cells, and B cells [6–8]. This study identifies that de novo polyamine synthesis is essential for cytokine‐stimulated NK cell metabolism and function.…”

Metabolic Dynamics of In Vitro CD8+ T Cell Activation

“…Recently, the importance of polyamines was described for several immune cell types. Polyamines were described to accumulate in NK cells and in CD4+ T cells following activation from naïve state [ 13 , 14 ] and this accumulation was shown to be required for appropriate effector function. In IL4 activated macrophages, blocking of polyamine biosynthesis blunted their activation [ 15 ].…”