Human CD8 T cell transcriptomic analysis from the three male siblings of similar ages with DJ-1 loss-of-function or heterozygous mutations

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. The family with Parkinson's disease (PD) carrying the c.192G>C mutation in the DJ-1 gene has been already described elsewhere and written informed consent for all participating individuals was obtained. The index patient (56 years) carries the homozygous c.192G>C mutation. The two unaffected siblings (60 and 63 years) are both heterozygous carriers of the c.192G>C mutation and were devoid of any clinical sign of PD at the recent neurological examination, as expected for this autosomal-recessively inherited condition. The experimental investigators were blind to the genotype of the three siblings until the flow cytometry analysis was complete. Fresh PBMCs of three sibilings were stained with anti-CD4 FITC (BD, 555346, also refer to Supplementary Table 4), anti-CD8 BV605 (BioLegend, 301040) and LIVE/DEAD™ Fixable Near-IR Dead Cell Stain Kit (ThermoFischer Scientific, L34976) for 30 min at 4 °C. Stained cells were washed with FACS buffer (PBS + 2%FBS) and total CD8 T cells were sorted using the BD Aria III. We analyzed total CD8 T cells using the Affymetrix Human Gene 2.0 ST Array. RNA samples were analysed at EMBL Genomics core facilities (Heidelberg. Germany). Array data was processed by Affymetrix Expression Console v1.4 using Exon-level analysis. No technical replicates were performed.