Abnormalities of age-related T cell senescence in Parkinson's disease

Abstract

Background: A wealth of evidence implicates both central and peripheral immune changes as contributing to the pathogenesis of Parkinson's disease (PD). It is critical to better understand this aspect of PD given that it is a tractable target for disease-modifying therapy. Age-related changes are known to occur in the immune system (immunosenescence) and might be of particular relevance in PD given that its prevalence rises with increasing age. We therefore sought to investigate this with respect to T cell replicative senescence, a key immune component of human ageing.

Methods: Peripheral blood mononuclear cells were extracted from blood samples from 41 patients with mild PD (Hoehn and Yahr stages 1-2, mean (SD) disease duration 4.3 (1.2) years) and 41 age- and gender-matched controls. Immunophenotyping was performed with flow cytometry using markers of T lymphocyte activation and senescence (CD3, CD4, CD8, HLA-DR, CD38, CD28, CCR7, CD45RA, CD57, CD31). Cytomegalovirus (CMV) serology was measured given its proposed relevance in driving T cell senescence.

Results: Markers of replicative senescence in the CD8+ population were strikingly reduced in PD cases versus controls (reduced CD57 expression (p = 0.005), reduced percentage of 'late differentiated' CD57_loCD28_hi cells (p = 0.007) and 'TEMRA' cells (p = 0.042)), whilst expression of activation markers (CD28) was increased (p = 0.005). This was not driven by differences in CMV seropositivity. No significant changes were observed in the CD4 population.

Conclusions: This study demonstrates for the first time that the peripheral immune profile in PD is distinctly atypical for an older population, with a lack of the CD8+ T cell replicative senescence which characterises normal ageing. This suggests that 'abnormal' immune ageing may contribute to the development of PD, and markers of T cell senescence warrant further investigation as potential biomarkers in this condition.

Keywords: Immune markers; Immunosenescence; Parkinson’s disease; T cells.

Fig. 1

CD8 immunophenotyping in PD cases (n = 41) versus age-matched controls (n = 41). a Following gating of the lymphocyte and singlet populations, CD8 cells were gated on the basis of high CD3 and CD8 staining, and the CD28_loCD57_hi subset was identified as a discrete population of CD8+ cells using 5% contour plots. Quadrant gates were used to divide the CD8 population into naïve, central memory, effector memory and TEMRA (terminally differentiated effector memory CD45RA+ve cells) subsets on pseudocolour dot plots. b Individual-level data for CD8 cell subsets (shown as percentage of lymphocytes). c Individual-level data for surface marker expression in CD8 T cells (median fluorescence intensity (MFI) ratio versus unstained lymphocytes). Horizontal lines denote means; *p < 0.05, **p < 0.01 in paired t tests

Fig. 2

CD8+ senescence markers in CMV-positive versus CMV-negative subjects. The figure shows CD57 expression on CD8+ lymphocytes (median fluorescence intensity (MFI) ratio versus unstained lymphocytes), CD8+ CD28_loCD57_hi cells (percentage of lymphocytes) and TEMRA cells (percentage of lymphocytes) in PD versus age-matched controls stratified by CMV seropositivity. Horizontal lines denote means; *p < 0.05 and ***p ≤ 0.001