Journal
CELL
Volume 184, Issue 16, Pages 4186-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2021.06.007
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Funding
- Sir Henry Wellcome Fellowship
- DFG grant under Germany's Excellence Strategy [CIBSS EXC-2189, 390939984]
- Max Planck Society
- Leibniz Prize
- Wellcome Trust
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Polyamine synthesis plays a critical role in T cell activation and differentiation, regulating CD4(+) T cells' function and epigenetic remodeling. Studies have revealed the significance of polyamine metabolism in controlling the fate of T-H cell subsets, with deficiency leading to aberrant expression of cytokines and transcription factors.
Polyamine synthesis represents one of the most profound metabolic changes during T cell activation, but the biological implications of this are scarcely known. Here, we show that polyamine metabolism is a fundamental process governing the ability of CD4(+) helper T cells (T-H) to polarize into different functional fates. Deficiency in ornithine decarboxylase, a crucial enzyme for polyamine synthesis, results in a severe failure of CD4(+) T cells to adopt correct subset specification, underscored by ectopic expression of multiple cytokines and lineage-defining transcription factors across T-H cell subsets. Polyamines control T-H differentiation by providing substrates for deoxyhypusine synthase, which synthesizes the amino acid hypusine, and mice in which T cells are deficient for hypusine develop severe intestinal inflammatory disease. Polyamine-hypusine deficiency caused widespread epigenetic remodeling driven by alterations in histone acetylation and a re-wired tricarboxylic acid (TCA) cycle. Thus, polyamine metabolism is critical for maintaining the epigenome to focus T-H cell subset fidelity.
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