PPARβ/δ-orchestrated metabolic reprogramming supports the formation and maintenance of memory CD8+ T cells

Sci Immunol. 2024 Aug 23;9(98):eadn2717. doi: 10.1126/sciimmunol.adn2717. Epub 2024 Aug 23.

Abstract

The formation of memory T cells is a fundamental feature of adaptative immunity, allowing the establishment of long-term protection against pathogens. Although emerging evidence suggests that metabolic reprogramming is crucial for memory T cell differentiation and survival, the underlying mechanisms that drive metabolic rewiring in memory T cells remain unclear. Here, we found that up-regulation of the nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) instructs the metabolic reprogramming that occurs during the establishment of central memory CD8+ T cells. PPARβ/δ-regulated changes included suppression of aerobic glycolysis and enhancement of oxidative metabolism and fatty acid oxidation. Mechanistically, exposure to interleukin-15 and expression of T cell factor 1 facilitated activation of the PPARβ/δ pathway, counteracting apoptosis induced by antigen clearance and metabolic stress. Together, our findings indicate that PPARβ/δ is a master metabolic regulator orchestrating a metabolic switch that may be favorable for T cell longevity.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes* / immunology
  • Immunologic Memory / immunology
  • Interleukin-15 / immunology
  • Interleukin-15 / metabolism
  • Memory T Cells / immunology
  • Metabolic Reprogramming
  • Mice
  • Mice, Inbred C57BL*
  • Mice, Knockout
  • Mice, Transgenic
  • PPAR delta* / immunology
  • PPAR delta* / metabolism
  • PPAR-beta* / immunology
  • PPAR-beta* / metabolism
  • Receptors, Cytoplasmic and Nuclear

Substances

  • PPAR-beta
  • PPAR delta
  • Interleukin-15
  • Ppard protein, mouse
  • Receptors, Cytoplasmic and Nuclear