Mitochondrial metabolism controls threshold of T cell activation or ‘How to fix an old engine’? 3441

Abstract Description T cell activation occurs by triggering of the T cell receptor (TCR) and induces spectrum of signaling, transcriptomic and metabolic changes. TCR triggering leads also to mitochondrial generation of low, non-toxic levels of reactive oxygen species (ROS) which serve as necessary “oxidative signal” regulating transcription, and therefore, T cell differentiation to specialized sub-types. In the elderly, T cells often cannot mount an immune response due to aberrant activation and exhausted phenotype. The mitochondrial theory of aging states that age-acquired mutations of mitochondrial DNA (mtDNA) lead to a vicious cycle of macromolecular damage due to elevated mitochondrial ROS. To investigate novel aspects of mitochondrial function in T cells we applied murine model of accelerated aging – mtDNA polymerase γ (PolG) ‘Mutator’ mouse. These mice gradually accumulate mtDNA mutations, which lead to pre-mature aging and reduced life span. We aimed to analyze the underlying causes of T cells disfunction in pre-maturely aged PolG Mutator mice. To this end, we combined bone-marrow (BM) transfer in vivo approaches (chimeras, LCMV infection) with metabolic flux analysis (MS-mediated monitoring of 13C-labelled isotopomers). We demonstrate unexpected consequences of mitochondrial impairment for T cell function. Importantly, we show how remodeling of mitochondrial metabolism controls threshold of T cell activation and how to genetically alleviate T cell dysfunction caused by accelerated aging. Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)