DJ‐1 depletion prevents immunoaging in T‐cell compartments

• Published in: EMBO reports Vol. 23; no. 3; pp. e53302 - n/a
• Main Authors: Zeng, Ni, Capelle, Christophe M, Baron, Alexandre, Kobayashi, Takumi, Cire, Severine, Tslaf, Vera, Leonard, Cathy, Coowar, Djalil, Koseki, Haruhiko, Westendorf, Astrid M, Buer, Jan, Brenner, Dirk, Krüger, Rejko, Balling, Rudi, Ollert, Markus, Hefeng, Feng Q
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.02.2022; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: Aging; Aging - genetics; Animals; CD8 antigen; CD8 T cells; Compartments; Depletion; EMBO19; EMBO24; Genetic factors; Humans; immune aging; Immune response; immunosenescence; Lymphocytes; Lymphocytes T; Mice; Mice, Knockout; Molecular modelling; Movement disorders; Neurodegenerative diseases; Oxidative phosphorylation; Oxidative Stress - genetics; PARK7 protein; PARK7/DJ‐1; Parkinson Disease - genetics; Parkinson's disease; Phosphorylation; Protein Deglycase DJ-1 - genetics; Protein Deglycase DJ-1 - metabolism; Sensitivity; Subpopulations; T cell receptors; T-Lymphocytes; immunosenescence; aging; PARK7; immune aging; CD8 T cells; PARK7/DJ-1
• ISSN: 1469-221X; 1469-3178; 1469-3178
• DOI: 10.15252/embr.202153302

Decline in immune function during aging increases susceptibility to different aging‐related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance of naïve/memory T‐cell subpopulations, still remain largely elusive. Here, we show that loss of DJ‐1 encoded by PARK7 /DJ‐1, causing early‐onset familial Parkinson’s disease (PD), unexpectedly diminished signs of immunoaging in T‐cell compartments of both human and mice. Compared with two gender‐matched unaffected siblings of similar ages, the index PD patient with DJ‐1 deficiency showed a decline in many critical immunoaging features, including almost doubled non‐senescent T cells. The observation was further consolidated by the results in 45‐week‐old DJ‐1 knockout mice. Our data demonstrated that DJ‐1 regulates several immunoaging features via hematopoietic‐intrinsic and naïve‐CD8‐intrinsic mechanisms. Mechanistically, DJ‐1 depletion reduced oxidative phosphorylation (OXPHOS) and impaired TCR sensitivity in naïve CD8 T cells at a young age, accumulatively leading to a reduced aging process in T‐cell compartments in older mice. Our finding suggests an unrecognized critical role of DJ‐1 in regulating immunoaging, discovering a potent target to interfere with immunoaging‐ and aging‐associated diseases. SYNOPSIS Deficiency in a key familial Parkinson’s disease gene, PARK7/DJ‐1, reduces immunoaging in T cell compartments of both human and mice at both cellular phenotypic and functional levels. DJ‐1 deficiency diminishes immunoaging in T cell compartments of an index PD patient. DJ‐1 depletion reduces signs of immunoaging in murine CD8 T cells. DJ‐1 depletion compromises OXPHOS and TCR sensitivity of naïve CD8 T cells starting at a young age, leading to relatively younger T‐cell compartments in older mice. DJ‐1 regulates several immunoaging features via a hematopoietic‐ and naïve CD8‐T‐cell‐intrinsic manner. Graphical Abstract Deficiency in a key familial Parkinson’s disease gene, PARK7/DJ‐1, reduces immunoaging in T cell compartments of both human and mice at both cellular phenotypic and functional levels.