Abstract
T cells undergo metabolic reprogramming with major changes in cellular energy metabolism during activation. In patients with mitochondrial disease, clinical data were marked by frequent infections and immunodeficiency, prompting us to explore the consequences of oxidative phosphorylation dysfunction in T cells. Since cytochrome c oxidase (COX) is a critical regulator of OXPHOS, we created a mouse model with isolated dysfunction in T cells by targeting a gene, COX10, that produces mitochondrial disease in humans. COX dysfunction resulted in increased apoptosis following activation in vitro and immunodeficiency in vivo. Select T cell effector subsets were particularly affected; this could be traced to their bioenergetic requirements. In summary, the findings presented herein emphasize the role of COX particularly in T cells as a metabolic checkpoint for cell fate decisions following T cell activation, with heterogeneous effects in T cell subsets. In addition, our studies highlight the utility of translational models that recapitulate human mitochondrial disease for understanding immunometabolism.
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•Patients with mitochondrial disease have an underappreciated immune phenotype•COX regulates activation and proliferation in T cells through apoptosis•Effector T cell subsets are differentially affected by COX deficiency•Mouse T cell COX deficiency produces immunodeficiency in vivo
Mitochondrial diseases are disorders of oxidative phosphorylation. Using mitochondrial disease as a model system, Tarasenko et al. demonstrate that cytochrome c oxidase deficiency differentially affects T cell effector subsets based on their bioenergetic requirements. Mouse T cell COX deficiency produces an immunodeficiency similar to that of patients with mitochondrial disease.
