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

Eur J Immunol. 2013 Dec;43(12):3355-60. doi: 10.1002/eji.201343571. Epub 2013 Sep 14.

Abstract

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.

Keywords: AKT signaling; Parkinson's disease; Peripheral T‐cell differentiation; Regulatory T (Treg) cells; T‐cell signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Cytosol / immunology*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Humans
  • Interleukin-2 / genetics
  • Interleukin-2 / immunology
  • Interleukin-2 Receptor alpha Subunit / genetics
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Lymphocyte Activation*
  • Mice
  • Mice, Knockout
  • Mitochondria / genetics
  • Mitochondria / immunology*
  • Parkinson Disease / genetics
  • Parkinson Disease / immunology
  • Parkinson Disease / pathology
  • Phosphorylation / genetics
  • Phosphorylation / immunology
  • Protein Kinases / genetics
  • Protein Kinases / immunology*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • Protein Kinases
  • PTEN-induced putative kinase
  • Proto-Oncogene Proteins c-akt