Polyamine metabolism is a central determinant of helper T cell lineage fidelity

Daniel J. Puleston, Francesc Baixauli, David E. Sanin, Joy Edwards-Hicks, Matteo Villa, Agnieszka M. Kabat, Marcin M. Kamiński, Michal Stanckzak, Hauke J. Weiss, Katarzyna M. Grzes, Klara Piletic, Cameron S. Field, Mauro Corrado, Fabian Haessler, Chao Wang, Yaarub Musa, Lena Schimmelpfennig, Lea Flachsmann, Gerhard Mittler, Nir YosefVijay K. Kuchroo, Joerg M. Buescher, Stefan Balabanov, Edward J. Pearce, Douglas R. Green, Erika L. Pearce

Research output: Contribution to journalArticlepeer-review

154 Scopus citations

Abstract

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 (TH) 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 TH cell subsets. Polyamines control TH 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 TH cell subset fidelity.

Original languageEnglish
Pages (from-to)4186-4202.e20
JournalCell
Volume184
Issue number16
DOIs
StatePublished - 5 Aug 2021
Externally publishedYes

Keywords

  • T cells
  • eIF5A
  • hypusine
  • immunity
  • immunometabolism
  • metabolism
  • polyamines

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