Dynamic Cardiolipin Synthesis Is Required for CD8+ T Cell Immunity

Summary 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.
Graphical Abstract
Highlights • Cardiolipin is essential for in vivo and in vitro CD8+ T cell responses • Active cardiolipin synthesis and remodeling occurs during T cell differentiation • Cardiolipin synthesis supports CD8+ TM cell development, metabolism, and function • T cell defects are evident in TAZ KO mice and in Barth syndrome patients
Corrado et al. show that the mitochondrial membrane-specific lipid cardiolipin is required for the metabolic plasticity that is essential for effective CD8+ T cell function. Cardiolipin-deficient CD8+ T cells fail to respond to pathogens and are not able to adapt to nutrient stress.