Mitochondrial and cytosolic roles of PINK1 shape induced regulatory T‐cell development and function

Mutations in PTEN‐induced kinase 1 (PINK1), a serine/threonine kinase linked to familial early‐onset Parkinsonism, compromise mitochondrial integrity and metabolism and impair AKT signaling. As the activation of a naïve T cell requires an AKT‐dependent reorganization of a cell's metabolic machinery, we sought to determine if PINK1‐deficient T cells lack the ability to undergo activation and differentiation. We show that CD4⁺ T cells from PINK1 knockout mice fail to properly phosphorylate AKT upon activation, resulting in reduced expression of the IL‐2 receptor subunit CD25. Following, deficient IL‐2 signaling mutes the activation‐induced increase in respiratory capacity and mitochondrial membrane potential. Under polarization conditions favoring the development of induced regulatory T cells, PINK1^?/? T cells exhibit a reduced ability to suppress bystander T‐cell proliferation despite normal FoxP3 expression kinetics. Our results describe a critical role for PINK1 in integrating extracellular signals with metabolic state during T‐cell fate determination, and may have implications for the understanding of altered T‐cell populations and immunity during the progression of active Parkinson's disease or other immunopathologies.