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

著者: 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 Piletič, Cameron S. Field, Mauro Corrado, Fabian Haessler, Chao Wang, Yaarub Musa, Lena Schimmelpfennig, Lea J. Flachsmann, Gerhard Mittler, Nir Yosef, Vijay K. Kuchroo, Joerg M. Buescher, Stefan Balabanov, Edward J. Pearce, Edward J. Pearce, Douglas R. Green, Erika L. Pearce, Erika L. Pearce - Cell 2021 被引用: 302

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.