Dynamic cardiolipin synthesis and remodeling is required for CD8+ T cell immunity
Mitochondria are plastic organelles, constantly adapting to the metabolic needs of a cell. This plasticity of mitochondria is critical to functional T cells, which modulate metabolism depending on antigen driven signals and environment. In this study we show that the dynamic balance between de novo synthesis and remodeling of cardiolipin, inner mitochondrial membrane-specific lipid, maintains CD8+ T cell metabolic and functional plasticity throughout the entire course of the immune response. T cells deficient for the cardiolipin synthetizing enzyme PTPMT1 have low cardiolipin and respond poorly to antigen because of a requirement for basal cardiolipin levels for T cell activation, but neither de novo cardiolipin synthesis, nor its Tafazzin-dependent remodeling, was needed for activation. Conversely, these two processes were vital when mitochondrial fitness was required during memory T cell differentiation or in glucose-restricted condition. We also found CD8+ T cell defects in a small cohort of patients with Barth syndrome. Therefore, dynamic regulation of cardiolipin de novo synthesis and remodeling are crucial for CD8+ T cell immunity.
Mauro Corrado1, Joy Edwards-Hicks1, Lea J. Flachsmann1, David E. Sanin1, Matteo Villa1, Francesc Baixauli1, Michal Stanczak1, Eve Anderson2, Mai Matsushita1, Andrea Quintana1, Jonathan D. Curtis1, Thomas Clapes3, Katarzyna M. Grzes1, Agnieszka M. Kabat1, Ryan Kyle1, Annette E. Patterson1, Maaike Jacobs1, Ramon Klein Geltink1, Borko Amulic5, Colin G. Steward5, Douglas Strathdee2, Eirini Trompouki3, David O’Sullivan1, Edward J. Pearce1,6, and Erika L. Pearce1.
- Department of Immunometabolism, Max-Planck Institute of Immunobiology and Epigenetics, 51 Stübeweg, 79108, Freiburg, Germany
- Cancer Research UK Beatson Institute, Glasgow, G61 1 BD, UK
- Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, 51 Stübeweg, 79108, Freiburg, Germany.
- Institute for Pharmaceutical Sciences, University of Freiburg, Albertstraße 25, 79104, Freiburg, Germany.
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.