Dynamic Cardiolipin Synthesis Is Required for CD8 + T Cell Immunity

Cell Metab. 2020 Dec 1;32(6):981-995.e7. doi: 10.1016/j.cmet.2020.11.003.

Abstract

Mitochondria constantly adapt to the metabolic needs of a cell. This mitochondrial plasticity is critical to T cells, which modulate metabolism depending on antigen-driven signals and environment. We show here that de novo synthesis of the mitochondrial membrane-specific lipid cardiolipin maintains CD8+ T cell function. T cells deficient for the cardiolipin-synthesizing enzyme PTPMT1 had reduced cardiolipin and responded poorly to antigen because basal cardiolipin levels were required for activation. However, neither de novo cardiolipin synthesis, nor its Tafazzin-dependent remodeling, was needed for T cell activation. In contrast, PTPMT1-dependent cardiolipin synthesis was vital when mitochondrial fitness was required, most notably during memory T cell differentiation or nutrient stress. We also found CD8+ T cell defects in a small cohort of patients with Barth syndrome, where TAFAZZIN is mutated, and in a Tafazzin-deficient mouse model. Thus, the dynamic regulation of a single mitochondrial lipid is crucial for CD8+ T cell immunity.

Keywords: Barth Syndrome; CD8 T cells; PTPMT1; Tafazzin; cardiolipin; immune memory; immunometabolism; mitochodria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / immunology*
  • Animals
  • Barth Syndrome / immunology*
  • Barth Syndrome / pathology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cardiolipins / immunology*
  • Cells, Cultured
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / immunology*
  • PTEN Phosphohydrolase / immunology*

Substances

  • Cardiolipins
  • Acyltransferases
  • TAFAZZIN protein, human
  • Ptpmt1 protein, human
  • PTEN Phosphohydrolase