Abstract
SummaryPolyamine 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.
Highlights
Upon activation, T cells proliferate to form effector cells that mediate immunity
We show that loss of polyamine synthesis leads to profound changes in the ability of CD4+ T cells to dependably differentiate into functionally distinct subsets
Polyamine biosynthesis is dynamically regulated in CD4+ T cells Polyamine metabolism requires ornithine decarboxylase (ODC) (Figure 1A)
Summary
For CD4+ helper T (TH) cells, this clonal expansion is linked to their differentiation into distinct subsets with specialized functions, which are critical for controlling pathogens and maintaining tissue homeostasis. A fourth subset of TH cell, regulatory T cells (Tregs), modulates immunity by dampening effector T cell activation and proliferation and expresses the TF Foxp (Fontenot et al, 2003). This partitioning of the CD4+ T cell response, such that pathogens drive distinct TH effector programs, necessitates that faithful TH differentiation is essential to mount an optimal immune response to any given threat
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