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

作者：Ellis Gavin I; Zhi Lianteng; Akundi Ravi; Bueeler Hansruedi; Marti Francesc^*

来源：European Journal of Immunology, 2013, 43(12): 3355-3360.

DOI：10.1002/eji.201343571

• AKT signaling
• Parkinson's disease
• Peripheral T-cell differentiation
• Regulatory T (Treg) cells
• T-cell signaling

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 naive 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.

• 出版日期2013-12