Methyltransferase Setd2 prevents T cell-mediated autoimmune diseases via phospholipid remodeling

Proc Natl Acad Sci U S A. 2024 Feb 20;121(8):e2314561121. doi: 10.1073/pnas.2314561121. Epub 2024 Feb 15.


Coordinated metabolic reprogramming and epigenetic remodeling are critical for modulating T cell function and differentiation. However, how the epigenetic modification controls Th17/Treg cell balance via metabolic reprogramming remains obscure. Here, we find that Setd2, a histone H3K36 trimethyltransferase, suppresses Th17 development but promotes iTreg cell polarization via phospholipid remodeling. Mechanistically, Setd2 up-regulates transcriptional expression of lysophosphatidylcholine acyltransferase 4 (Lpcat4) via directly catalyzing H3K36me3 of Lpcat4 gene promoter in T cells. Lpcat4-mediated phosphatidylcholine PC(16:0,18:2) generation in turn limits endoplasmic reticulum stress and oxidative stress. These changes decrease HIF-1α transcriptional activity and thus suppress Th17 but enhance Treg development. Consistent with this regulatory paradigm, T cell deficiency of Setd2 aggravates neuroinflammation and demyelination in experimental autoimmune encephalomyelitis due to imbalanced Th17/Treg cell differentiation. Overall, our data reveal that Setd2 acts as an epigenetic brake for T cell-mediated autoimmunity through phospholipid remodeling, suggesting potential targets for treating neuroinflammatory diseases.

Keywords: Setd2; autoimmunity; lysophosphatidylcholine acyltransferase 4; phosphatidylcholine.

MeSH terms

  • Autoimmune Diseases*
  • Cell Differentiation
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Phospholipids*
  • T-Lymphocytes / metabolism


  • Phospholipids
  • Histones