Aging of T lymphocytes has detrimental effects on the health of older individuals; rendering them susceptible to cancer, infection, and unopposed tissue inflammation. Older T cells are prone to differentiate into inflammatory effector cells, rapidly invading into peripheral tissues and promoting inflammatory tissue damage. Multiple biologic processes have been implicated in mediating T cell aging; including defective DNA repair, telomeric damage, membrane restructuring into invasive protrusions and reprogramming of cellular bioenergetics. T cell aging is accelerated by 20-30 years in patients with the inflammatory syndrome rheumatoid arthritis (RA), providing an excellent model system to study molecular, structural and behavioral abnormalities in old T cells. Work supported during the previous funding period has identified the DNA nuclease MRE11A as a key player in T cell aging. T cells from RA patients and from older healthy donors share the transcriptional repression of MRE11A. T cells low in MRE11A protein accumulate damaged telomeres and induce robust tissue inflammation with a signature of uncontrolled innate and adaptive immunity. Preliminary data show that MRE11Alow T cells also lack expression of the nuclease in mitochondria, leading to oxidative damage and cytoplasmic leakage of mitochondrial DNA (mtDNA). In the cytoplasm, oxidized mtDNA promotes NLRP3 inflammasome assembly, triggers caspase 1 activation and ultimately induces T cell lytic death. Here, we examine the hypothesis that mitochondrial stress is a driver of T cell aging and that the age-related decline of the DNA repair nuclease MRE11A exposes T cells to mitochondrial DNA leakage, inflammasome activation and ultimately to pyroptotic death. We have assembled key enabling resources to mechanistically study how mitochondrial MRE11A protects T cells from aging; including a large cohort of RA patients in whom T cells are pre-aged and a chimeric mouse model in which tissue inflammation is induced in engrafted human synovium to corroborate in vitro data by in vivo studies.
Aim 1 examines mechanistically how MRE11A affects mitochondrial function, generation of ATP and ROS, glucose utilization and lipogenesis.
The aim will connect mitochondrial DNA repair to oxygen consumption in the electron transfer chain and acetyl-CoA oxidation in the tricarboxylic acid cycle.
Aim 2 investigates how MRE11A guides a mitochondrial stress defense program by preventing mtDNA release into the cytoplasm. In loss-of-function and gain-of-function experiments we will probe how MRE11A regulates inflammasome assembly, caspase 1 activation and T cell pyroptosis.
Aim 3 will identify mechanisms through which MRE11A deficiency induces tissue inflammation. We will test how caspase 1-dependent cleavage of the pro-inflammatory cytokines IL-1? and IL-18 and of the membrane pore former gasdermin D drive tissue damage. These experiments will explore in vitro and in vivo how failed mitochondrial DNA repair causes T cell lysis, release of alarmins into the extracellular space and initiation of noninfectious inflammation.
The immune system changes profoundly with progressive age, leaving the elderly susceptible to cancer, infection and tissue inflammation. Immune aging occurs prematurely in patients with rheumatoid arthritis and is associated with defects in DNA repair and with reprogramming of cellular metabolism. Here, we study the role of mitochondria and of mitochondrial DNA repair in immune aging.
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