Next Article in Journal
Qualitative Study on Important Elements of Life for Japanese and Thai Older Adults
Previous Article in Journal
Factors Associated with Annual Influenza Vaccination Uptake in U.S. Older Adults from 2019 to 2020
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Higher Frequencies of T-Cells Expressing NK-Cell Markers and Chemokine Receptors in Parkinson’s Disease

Fairfax Centre, Kidlington OX5 2PB, UK
Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, German Center for Neurodegenerative Diseases, University of Tübingen, 72076 Tübingen, Germany
Experimental Medicine and Diagnostics, Global Exploratory Development, UCB Biopharma SPRL, 1070 Brussels, Belgium
Consultancy Neuropharm, 41470 Neuss, Germany
Section for Dementia Research, Department of Psychiatry and Psychotherapy, University of Tübingen, 72076 Tübingen, Germany
Department of Immunology, University of Tübingen, 72076 Tübingen, Germany
Health Sciences North Research Institute, Sudbury, ON P3E 2H2, Canada
Department of Neurology, Kiel University, 24105 Kiel, Germany
Novartis Institutes for BioMedical Research, CH-4056 Basel, Switzerland
Author to whom correspondence should be addressed.
J. Ageing Longev. 2023, 3(1), 1-10;
Received: 1 October 2022 / Revised: 16 December 2022 / Accepted: 19 December 2022 / Published: 22 December 2022


Immune cells are thought to be involved in a destructive cycle of sterile cerebral inflammatory responses in neurodegenerative diseases such as Parkinson’s Disease (PD). Despite their peripheral origin, immune cells may enter the CNS due to impaired blood–brain barrier function and may potentially contribute to neuronal damage. Hence, specific characteristics of peripherally activated immune cells could help in understanding neurodegeneration in PD and could potentially serve as accessible disease markers. To investigate immune cell activation status, the expression of receptors for cell surface molecules CD161, NKG2A, NKG2C and NKG2D as well as chemokine receptors CCR6, CXCR2, CXCR3 and CCR5 associated with neurodegenerative diseases was investigated. The frequencies of peripheral CD8+ T-cells expressing the inhibitory and activating receptors NKG2A and NKG2C, and the activating receptor NKG2D were higher in PD patients than in healthy matched controls. The frequencies of NKG2C+CD8− cells were also higher, whereas the frequencies of CD161+ cells were not significantly different. Of the chemokine receptor-expressing cells, only the proportion of CD4−CD56+CCR5+ T-cells was higher in PD patients than in the controls. These observations support the hypothesis that an imbalance in the activation state of T-cells plays a role in the pathological processes of PD and suggest that peripheral blood immune cell phenotypes could be specific early markers for inflammation in PD.

1. Introduction

Ageing and neurodegeneration are both associated with low-grade chronic inflammation as measured by the levels of different serum molecules [1,2,3,4,5]. It has been reported that inflammatory factors secreted by activated microglia, astrocytes, neurons, T-cells and mast cells may all lead to neuroinflammation and, further, neurodegeneration and that, for microglia at least, secretion is greater in older adults [5]. These effects are exacerbated by a defective blood–brain barrier (BBB) in older adults [5], including PD patients [6]. The levels of cytokines such as IL-6 and TNF-alpha are reportedly associated with higher mortality as well as with functional decline in older adults [1,2,3]. Neuroinflammatory processes have also been suggested to participate in the pathogenesis of Parkinson’s Disease (PD). Microglia in the substantia nigra have been shown to produce proinflammatory cytokines such as IL-6, TNF-alpha and IL-1beta; the concentrations of these proinflammatory factors are also increased in the striatum [7] and in cerebrospinal fluid (CSF) in PD [8,9], and there are reports of elevated TNF-alpha and IL-6 in patients’ plasma [10,11]. Microglia-mediated neuroinflammation is thought to play an important role in the pathogenesis of PD, but it is not clear whether the systemic inflammatory markers in patients represent a cause or a consequence of the ongoing neurodegenerative process.
Currently, it is hypothesized that abnormal proinflammatory cytokine levels in the periphery (e.g., TNF-alpha and IL-6) reflect the presence of a cerebral inflammatory process. The roles of TNF-alpha and IL-6 are particularly well-established in acute inflammation and as mediators of lymphocyte differentiation, including B and T lymphocytes and NK-cells. In line with this, frequencies of NK-cells were reported to be higher in PD patients than controls [12,13]. NK-cells have also been found in human postmortem PD substantia nigra [14] and PD mouse model brains [15]. Potential actions of NK-cells in PD brains include the degradation of α-syn aggregates, support for repairing damaged neurons or glia, the modulation of inflammation by interacting with brain cells and by influencing other leukocytes infiltrating the CNS [16].
Proposed mechanisms responsible for PD pathology include altered expression of NK-cell receptor ligands on neurons and microglia influencing the activation status of the NK-cells [16]. The NK-cell surface receptors NKG2A, NKG2C and NKG2D can also be expressed on T-cells [17,18]. NKG2A expression is related to an effector phenotype and contributes to long-term maintenance of CD8+ T-cells in chronic disease [19]. T-cells activated via NKG2A suppress TNF production and cytotoxic function of CD8+ T-cells [20], whereas NKG2C, NKG2D and CD161 ligation results in increased cytokine production and higher levels of cytotoxic molecules, such as granzyme B and perforin [21]. CD161 expression characterizes T-cells that, after activation, produce greater quantities of proinflammatory cytokines, such as IFN-gamma and IL-17, than their CD161- counterparts [22,23]. The frequencies of NK-cells carrying NKG2A and NKG2D were reported to be different in PD patients relative to the controls in some studies [12,13], while others found lower NKG2A expression in PD and no difference in NKG2D+ NK-cells [12]. NKG2C+ cells and T-cells expressing CD161 have also been implicated in the pathogenesis of another neurodegenerative disease, multiple sclerosis [24]. Although PD and MS are very different diseases, this implies that, in general, NKG2C+ cells can affect the brain; hence, we were encouraged to investigate whether these cells are elevated in PD and possibly contribute to pathology also in this disease. Different T-cell immune signatures in PD have been reported, as, e.g., less late differentiated CD8+ T-cells in PD patients compared to the controls [25].
CD161+CD8+ IL-17-producing T-cells express chemokine receptors such as CCR6 and CCR2 [26]. This provides for further potential associations with diseases of the brain because CCR6 may be related to the homing of T-cells to the brain [27] and to the entry of IL-17-producing cells into the brain in autoimmune encephalomyelitis [28]. Along these lines, IL-17-producing CD4+ Th17 cells have been reported to be significantly increased in PD patients [29]. The increased expression of CCR6 on blood-derived brain cells in a murine model of inflammation in pre-Alzheimer’s-like disease is also consistent with this notion [30]. CCR6 expression is also increased in PBMCs of Alzheimer’s disease (AD) patients [30,31,32]. Another chemokine receptor, CCR5, plays a role in BBB transport [33,34]. Its deficiency results in the activation of astrocytes and Aβ deposition [35]. Therefore, it might represent a possible route through the BBB into the brain [35,36]. T-cells expressing the chemokine receptor CXCR3 have been reported to be decreased in PD patients [13]. CXCR3-positive cells have increased cytokine production capacity and can promote the development of cytotoxicity. Migration through endothelial cell layers, as part of the BBB, has been observed in this context [37], especially in an inflammatory environment where activated astrocytes secrete chemokines recruiting peripheral immune cells into the brain [38]. A study focusing on alterations in the levels of chemokines secreted by PBMCs from PD patients showed that these chemokines were more highly expressed relative to controls, and correlated with the patients’ UPDRS III score [39]. In early PD stages, the infiltration of cytotoxic CD8+ T-cells into the substantia nigra has also been reported [40].
In light of the above findings, to investigate the specific activation status of T-cells in a well-characterized and homogeneous cross-sectional cohort focusing on early PD patients, four receptors (NKG2A, NKG2C, NKG2D and CD161) were selected, and to characterize a possible role of chemotaxis, three receptors (CCR5, CCR6 and CXCR3) that have been proposed to play critical roles in PD were chosen. Additionally, the proportion of NK-cells was compared between PD patients and controls according to their maturation stages (CD56highCD16low marking immature NK cells, CD56lowCD16high marking mature, and CD56lowCD16highCD57+ late-stage or terminal).

2. Materials and Methods

2.1. Cohorts

Eighteen PD patients and twenty-four controls were recruited from the outpatient clinic at the Department of Neurodegenerative Diseases of the University of Tübingen, Germany, and clinical data were collated (Table S1). The study was approved by the Ethics Committee of the Medical Faculty of the University of Tübingen (480/2015BO2). All participants provided written informed consent. PD was diagnosed according to the United Kingdom Brain Bank Society Criteria. Control individuals were assessed as having no neurological disease or inflammatory disease and were chosen to be age and sex-matched to the PD patients. PD patients were chosen to represent a homogeneous cohort with very early disease state (blood withdrawal 0–3 years after disease onset, mean 1.89 years) and to have the akinetic-rigid subtype of PD. Plasma was obtained and CMV serostatus determined via an anti-CMV IgG ELISA (Genesis Diagnostics CMV IgG ELISA kit GD84, Omega Diagnostics, Reinbeck, Germany).

2.2. Surface Marker Staining of PBMCs

PBMCs were isolated from EDTA-whole blood by Ficoll-Hypaque (Linaris, Mannheim, Germany) gradient centrifugation. PBMCs were frozen at −80 °C in 10% DMSO (Serva, Heidelberg, Germany) and 20% FBS (Sigma, Pittsburgh, PA, USA) and subsequently stored in liquid nitrogen. After thawing, non-specific antibody binding was blocked with 1% Gamunex (human IgG from Talecris, Clayton, NC, USA). Cells were then stained with ethidium monoazide bromide (Biotium, Fremont, CA, Canada) for live-dead discrimination. Surface marker staining of 2 × 106 PBMCs in PBS (PAA, Pasching, Austria) with 2% (v/v) FBS (Sigm, Pittsburgh, PA, USA), 2 mM EDTA (Serva, Heidelberg, Germany) and 0.01% (w/v) NaN3 (Sigma, Pittsburgh, PA, USA) was performed using the antibodies shown in Table S2. Markers were chosen to identify T-cells (CD3+), NK-cells (CD16+CD56+), their activation and differentiation status (CD161, NKG2A, NKG2C, NKG2D, CD57) and their expression of selected chemokine receptors (CCR5, CCR6, CXCR3). Measurements were performed with a BD LSRII flow cytometer and DIVA 6.1 software. To ensure performance quality, control BD CS&T tracking beads and BD 8 peak rainbow beads were applied, and for each measurement run, cells from the same batch of a control donor were included as a standard biological control. To determine frequencies of immune cells and their expression of markers, FlowJo software version 7.2.5 (Treestar) was used with the gating strategy shown in Figures S1–S8.

2.3. Statistics

Statistical analysis was performed using SPSS software. Age and length of PBMC storage were compared between PD patients and controls using the t-Test, gender and CMV serostatus using Pearson Chi Square Test. The analysis included the cell phenotypes CD8+/CD8−, CD4+/CD4− and CD56+/CD56− T-cells and CD56highCD16low, CD56lowCD16high and CD56lowCD16highCD57+ NK-cells. Age, gender, length of PBMC storage and CMV serostatus were not significantly different between PD and control samples (Table S1) and were thus not included as covariates. The proportions of cells expressing the receptors of interest were compared between the groups of PD patients and controls using Mann–Whitney U Tests. For NKG2D, expression was determined as median fluorescence intensity of staining with the conjugated antibody and used for comparison between PD patients and controls.

3. Results

3.1. T-Cell Activation Status

The frequencies of CD8+ T-cells expressing the inhibitory receptor NKG2A in relation to the total % of CD3+ T-cells were significantly higher in PD patients (0.58%) compared to controls (0.35%; p = 0.021; Figure 1a), as were the frequencies of those cells expressing the activating receptor NKG2C in relation to % CD3+ cells (0.30%) compared to controls (0.18%, p = 0.047; Figure 1b). The latter was also the case for CD8−T-cells (PD patients 0.35%; controls 0.28%; p = 0.036; Figure 1c). The density of expression of the activating receptor NKG2D on CD8+ T-cells was higher in patients than in controls as analyzed by median fluorescence intensity (2103-vs.-1894, p = 0.04; Figure 1d). The other investigated activating receptor, CD161, showed no statistically significant difference between PD patients and controls when analyzing the median frequencies of positive cells.

3.2. Chemokine Receptor Expression

Of the three investigated chemokine receptors, the frequencies of T-cells and NKT-cells expressing CCR6 or CXCR3 were not significantly different between PD patients and controls. Only the proportion of CD4-CD56+ NKT-cells expressing CCR5 was found to be higher in PD patients (2.06% in PD patients and 0.81% in controls; p = 0.013; Figure 1e), although significance was reduced to a trend when %CD3+CD56− T-cells were used as the reference population instead of %CD45+ cells. Median frequencies of CCR5-expressing CD4+ T-cells did not reveal a difference between PD patients and controls, in neither the activated (CD56+) nor not activated states (CD56−) (Figure S9). Regarding NK-cells, median frequencies of CCR5-expressing mature NK-cells did not differ significantly between PD patients and controls (Table 1).

3.3. NK-Cell Differentiation States

No significant differences between PD patients and controls were found for frequencies of either immature NK-cells (CD3-CD56highCD16low), mature NK-cells (CD3-CD56lowCD16high) or late-stage NK-cells (CD3-CD56lowCD16highCD57+) (Table 1).

4. Discussion

4.1. NK-Cell Receptor-Expressing T-Cells in PD Patients vs. Controls

Here, we report a higher proportion of T-cells expressing the activating receptor NKG2C and a higher density of expression of the activating receptor NKG2D on circulating lymphocytes from PD patients relative to age- and sex-matched controls. However, a higher frequency of T-cells expressing the inhibitory receptor NKG2A was also present. These observations suggest that an imbalance in the activation states has occurred. NKG2A expression is enhanced by anti-inflammatory cytokines [41] possibly secreted to restore inflammatory equilibrium after viral infection. In PD, NKG2A-expressing T-cells might play a similar role, i.e., to dampen inflammation. NKG2C was previously described as an alternative activating receptor promoting proliferation and effector functions of cytotoxic T-cells [42]. Its expression (as well as that of other NKG2 receptors) has been reported to be elevated in conditions of CMV infection, of ageing or of chronic immune stimulation during disease [43]. Once they infiltrate the brain, cytotoxic NKG2C+ CD4+ T-cells can contribute to tissue damage, as shown by the example of oligodendrocyte damage observed in studies on multiple sclerosis [21]. These cells co-expressed CD56 and NKG2D receptors and produced more cytotoxic molecules (FasL, granzyme B and perforin) than NKG2C-negative T-cells [21]. In a mouse PD model, cytotoxic CD4+ T-cells contributed to neurodegeneration via the Fas/FasL pathway [44]. The dysregulation of NKG2D was proposed to lead to autoreactive T cell stimulation and to promote a self-perpetuating pathology in autoimmune disease [45]. Both NKG2C and NKG2D are linked to a cytotoxic pathway, and our study indicates that they might be markers of an inflammatory state in PD pathology that originates from the periphery.

4.2. Chemokine Receptor Expression on T-Cells

Inflammation at the BBB, e.g., induced by proinflammatory cytokines secreted by microglia [39], can result in structural changes at cell–cell junctions and the upregulated expression of adhesion molecules. This leads to increased leukocyte transmigration [46]. Chemokines are important for crossing the BBB—one such is CCL5 (also known as RANTES). It is one of the many inflammatory mediators secreted by activated microglia, astrocytes, neurons, T-cells and mast cells in the context of neurodegenerative diseases [47]. CCL5 was found at higher levels in PD patients compared to a control group [48] and was even higher in PD patients treated with levodopa [49]. In addition, serum CCL5 levels correlated with the UPDRS III score [48], the Hoehn–Yahr score and disease duration [50]. Reale et al. postulated that the “systemic presence of CCL5 in PD may reflect both a central and/or peripheral source of activation” [51]. The corresponding receptor CCR5 is a major driver of brain infiltration by T-cells via the BBB. It is expressed by T-cells, which were demonstrated to cross an in vitro BBB model [34]. Furthermore, these CCR5-expressing cells have been found in MS lesions [34], and CCR5 and CCL5 expression was increased upon stimulation with Aβ, a marker for Alzheimer pathology [51,52]. Similarly, in PD, alpha-synuclein might be able to induce CCR5 expression, but this remains speculative. A recent study found CCR5 enrichment among transcriptomic signatures previously associated with PD [53]. In addition, work on a mouse model of PD revealed that stimulation of TH17 cells with alpha-synuclein could cause neuronal cell death in the substantia nigra (SN) [54]. More research would be needed to determine whether CD4+ TH17 cells exhibit increased chemokine receptor expression. As a possible indication of increased migration of peripheral cells, we found higher frequencies of T-cells expressing the chemokine receptor CCR5 (CD56+CD4-CCR5+ T-cells) in PD patients than in controls. Brain-infiltrating T-cells may induce excessive microglial inflammation and oxidative stress, promoting further neurodegeneration in PD [55]. Additionally, CCR5 expression correlates with inflammation mediated by type 1 T helper cells (TH1) [56,57], which mainly produce proinflammatory cytokines and support macrophages and cytotoxic T-cells, whereas Type 2 (TH2) cells primarily produce anti-inflammatory cytokines and induce humoral responses. In chronic inflammation, the fine balance of the TH1 and TH2 system may be shifted towards the TH1 pathway, and NK-cells and T-cells may be activated. This shift towards the TH1 pathway might be a general finding in PD. Interestingly, an available CCR5 antagonist has already been proposed as a possible drug for neuroinflammatory diseases, with a suggested mechanism of action focusing on hindering the migration of CCR5+ cells into the CNS [58]. In this context, limiting the impact of the intervention to CCR5 on peripheral cells would need to be considered because of the possibility that bidirectional interactions between neurons and glial cells via CCR5 in the brain may be beneficial for dopaminergic neuron survival [59]. These findings parallel the observation of elevated frequencies and surface levels of migration markers CCR2 and CD11b on classical and intermediate monocytes in early Parkinson’s disease, which correlate with worse cognition [60]. Thus, the current study provides evidence that peripheral activation of inflammatory processes could potentially cause cerebral cell death via transendothelial activation of cerebral inflammatory responses. As our data show the imbalance in the activation of T-cells in the periphery, further data are needed to confirm their direct intracerebral effects.

4.3. Observations on NK-Cells

We also investigated the NK-cell frequencies, but we did not find any significant differences between PD patients and controls. Our results stand in contrast to three previous studies [12,13,61] that found elevated frequencies of NK-cells in PD patients. These studies found a positive correlation between disease duration and NK-cell frequency or activity. Compared to these cohorts of PD patients, our cohort was in a very early disease stage, since they were recruited only up to 3 years after disease onset (mean 1.89 years), which is in line with the hypothesis that relevant immune changes occur early on, are possibly causative, but are less pronounced at later stages [62]. Hence, if the frequency of NK-cells is similar in PD patients and controls in early disease stage and increases, and then decreases again with disease progression, the potential of this parameter in serving as a dynamic marker of progression could be of value in future studies. Consistent with this notion, a different study found a significant elevation of NK-cell frequencies in late-onset PD patients compared to healthy controls, but this did not reach significance when comparing early onset PD patients to controls [63].

5. Conclusions

The specific pattern of peripherally activated T-cells in the blood of early PD patients, as detected in this study, suggests a mechanism contributing to neuronal degeneration in PD that could potentially be included in a panel of markers for early disease diagnosis. The present data confirm the complexity of inflammatory processes in PD. Further studies on longitudinal samples might aid in better deciphering these processes. Parallel with disease severity, further studies should also consider the influence of potential confounders such as ethnic variations, as discussed recently [63].

Supplementary Materials

The following supporting information can be downloaded at, Figure S1. Gating strategy for the populations of panel 1 part 1. Figure S2. Gating strategy for the populations of panel 1 part 2. Figure S3. Gating strategy for the populations of panel 1 controls. Figure S4. Gating strategy for the populations of panel 1 controls. Figure S5. Gating strategy for the populations of panel 2 part 1. Figure S6. Gating strategy for the populations of panel 2 part 2. Figure S7. Gating strategy for the populations of panel 2 part 3. Figure S8. Gating strategy for the populations of panel 2 part 4. Figure S9. Frequencies of chemokine receptor-expressing CD4+ T-cells (a) and CD4+ NKT-cells (b) among CD45+ cells displayed as Tukey plots Mann–Whitney U Tests comparing PD patients (PD) and controls (C) did not reveal any significant differences. Table S1. Cohort Summary. Table S2. Monoclonal antibodies employed.

Author Contributions

Conceptualization, D.G., G.P., A.N.d.C., D.S. and W.M.; methodology, L.Ö., D.G. and M.C.T.d.S.; formal analysis, L.Ö. and C.S.; investigation, L.Ö., C.D. and D.G.; resources, C.D. and W.M.; data curation, L.Ö., D.G., C.S., C.D. and W.M.; writing—original draft preparation, C.S. and D.G.; writing—review and editing, M.C.T.d.S., G.P., D.S., W.M., D.B. and A.N.d.C.; visualization, C.S.; supervision, G.P. and W.M.; project administration, D.B., A.N.d.C., D.S. and W.M.; funding acquisition, G.P., A.N.d.C. and W.M. All authors have read and agreed to the published version of the manuscript.


This work was supported by grants from the German Federal Ministry for Education and Research (BMBF) within the BioPharma initiative Neuroallianz, project D13 B (grants 16GW0066K and 16GW0067) and by UCB Pharma GmbH (Monheim, Germany). We acknowledge support by Deutsche Forschungsgemeinschaft.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Medical Faculty of the University of Tübingen (480/2015BO2).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

The data presented in this study are available from the corresponding author upon request.


Samples were obtained from the Neuro-Biobank of the University of Tübingen, Germany. This biobank is supported by the local University, the Hertie Institute and the DZNE.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Adriaensen, W.; Matheï, C.; Vaes, B.; van Pottelbergh, G.; Wallemacq, P.; Degryse, J.-M. Interleukin-6 as a first-rated serum inflammatory marker to predict mortality and hospitalization in the oldest old: A regression and CART approach in the BELFRAIL study. Exp. Gerontol. 2015, 69, 53–61. [Google Scholar] [CrossRef] [PubMed]
  2. Adriaensen, W.; Mathei, C.; Van Pottelbergh, G.; Vaes, B.; Legrand, D.; Wallemacq, P.; Degryse, J.-M. Significance of serum immune markers in identification of global functional impairment in the oldest old: Cross-sectional results from the BELFRAIL study. AGE 2014, 36, 457–467. [Google Scholar] [CrossRef] [PubMed][Green Version]
  3. Bruunsgaard, H. Effects of tumor necrosis factor-alpha and interleukin-6 in elderly populations. Eur. Cytokine Netw. 2002, 13, 389–391. [Google Scholar] [PubMed]
  4. Ferrari, C.C.; Tarelli, R. Parkinson’s Disease and Systemic Inflammation. Park. Dis. 2011, 2011, 436813. [Google Scholar] [CrossRef] [PubMed][Green Version]
  5. Kempuraj, D.; Thangavel, R.; Natteru, P.A.; Selvakumar, G.P.; Saeed, D.; Zahoor, H.; Zaheer, S.; Iyer, S.S.; Zaheer, A. Neuroinflammation Induces Neurodegeneration. J. Neurol. Neurosurg. Spine 2016, 1, 1003. [Google Scholar]
  6. Kortekaas, R.; Leenders, K.L.; Van Oostrom, J.C.H.; Vaalburg, W.; Bart, J.; Willemsen, A.T.M.; Hendrikse, N.H. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann. Neurol. 2005, 57, 176–179. [Google Scholar] [CrossRef]
  7. Mogi, M.; Harada, M.; Kondo, T.; Riederer, P.; Inagaki, H.; Minami, M.; Nagatsu, T. Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients. Neurosci. Lett. 1994, 180, 147–150. [Google Scholar] [CrossRef]
  8. Blum-Degena, D.; Müller, T.; Kuhn, W.; Gerlach, M.; Przuntek, H.; Riederer, P. Interleukin-1β and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neurosci. Lett. 1995, 202, 17–20. [Google Scholar] [CrossRef]
  9. Muller, T.; Blum-Degen, D.; Przuntek, H.; Kuhn, W. Interleukin-6 levels in cerebrospinal fluid inversely correlate to severity of Parkinson’s disease. Acta Neurol. Scand. 1998, 98, 142–144. [Google Scholar] [CrossRef]
  10. Dobbs, R.J.; Charlett, A.; Purkiss, A.G.; Dobbs, S.M.; Weller, C.; Peterson, D.W. Association of circulating TNF-α and IL-6 with ageing and parkinsonism. Acta Neurol. Scand. 1999, 100, 34–41. [Google Scholar] [CrossRef]
  11. Dufek, M.; Hamanová, M.; Lokaj, J.; Goldemund, D.; Rektorová, I.; Michálková, Z.; Sheardová, K.; Rektor, I. Serum inflammatory biomarkers in Parkinson’s disease. Park. Relat. Disord. 2009, 15, 318–320. [Google Scholar] [CrossRef] [PubMed]
  12. Mihara, T.; Nakashima, M.; Kuroiwa, A.; Akitake, Y.; Ono, K.; Hosokawa, M.; Yamada, T.; Takahashi, M. Natural killer cells of Parkinson’s disease patients are set up for activation: A possible role for innate immunity in the pathogenesis of this disease. Parkinsonism Relat. Disord. 2008, 14, 46–51. [Google Scholar] [CrossRef] [PubMed]
  13. Niwa, F.; Kuriyama, N.; Nakagawa, M.; Imanishi, J. Effects of peripheral lymphocyte subpopulations and the clinical correlation with Parkinson’s disease. Geriatr. Gerontol. Int. 2012, 12, 102–107. [Google Scholar] [CrossRef] [PubMed]
  14. Earls, R.H.; Menees, K.B.; Chung, J.; Gutekunst, C.-A.; Lee, H.J.; Hazim, M.G.; Rada, B.; Wood, L.B.; Lee, J.-K. NK cells clear α-synuclein and the depletion of NK cells exacerbates synuclein pathology in a mouse model of α-synucleinopathy. Proc. Natl. Acad. Sci. USA 2020, 117, 1762–1771. [Google Scholar] [CrossRef]
  15. Earls, R.; Menees, K.B.; Chung, J.; Barber, J.; Gutekunst, C.-A.; Hazim, M.G.; Lee, J.-K. Intrastriatal injection of preformed alpha-synuclein fibrils alters central and peripheral immune cell profiles in non-transgenic mice. J. Neuroinflamm. 2019, 16, 250. [Google Scholar] [CrossRef][Green Version]
  16. Earls, R.H.; Lee, J.-K. The role of natural killer cells in Parkinson’s disease. Exp. Mol. Med. 2020, 52, 1517–1525. [Google Scholar] [CrossRef]
  17. Freishtat, R.J.; Mitchell, L.W.; Ghimbovschi, S.D.; Meyers, S.B.; Hoffman, E.P. NKG2A and CD56 Are Coexpressed on Activated TH2 but Not TH1 Lymphocytes. Hum. Immunol. 2005, 66, 1223–1234. [Google Scholar] [CrossRef][Green Version]
  18. Graham, C.M.; Christensen, J.R.; Thomas, D.B. Differential induction of CD94 and NKG2 in CD4 helper T cells. A consequence of influenza virus infection and interferon-gamma? Immunology 2007, 121, 238–247. [Google Scholar] [CrossRef]
  19. Cush, S.S.; Flaño, E. KLRG1+NKG2A+ CD8 T Cells Mediate Protection and Participate in Memory Responses during γ-Herpesvirus Infection. J. Immunol. 2011, 186, 4051–4058. [Google Scholar] [CrossRef][Green Version]
  20. Piet, B.; De Bree, G.J.; Smids-Dierdorp, B.S.; Van Der Loos, C.M.; Remmerswaal, E.; von der Thusen, J.; Van Haarst, J.M.W.; Eerenberg, J.P.; Brinke, A.T.; Van Der Bij, W.; et al. CD8+ T cells with an intraepithelial phenotype upregulate cytotoxic function upon influenza infection in human lung. J. Clin. Investig. 2011, 121, 2254–2263. [Google Scholar] [CrossRef][Green Version]
  21. Zaguia, F.; Saikali, P.; Ludwin, S.; Newcombe, J.; Beauseigle, D.; McCrea, E.; Duquette, P.; Prat, A.; Antel, J.P.; Arbour, N. Cytotoxic NKG2C+ CD4 T Cells Target Oligodendrocytes in Multiple Sclerosis. J. Immunol. 2013, 190, 2510–2518. [Google Scholar] [CrossRef] [PubMed]
  22. Björkander, S.; Hell, L.; Johansson, M.A.; Forsberg, M.M.; Lasaviciute, G.; Roos, S.; Holmlund, U.; Sverremark-Ekström, E. Staphylococcus aureus-derived factors induce IL-10, IFN-γ and IL-17A-expressing FOXP3+CD161+ T-helper cells in a partly monocyte-dependent manner. Sci. Rep. 2016, 6, 22083. [Google Scholar] [CrossRef] [PubMed][Green Version]
  23. Pesenacker, A.M.; Bending, D.; Ursu, S.; Wu, Q.; Nistala, K.; Wedderburn, L. CD161 defines the subset of FoxP3+ T cells capable of producing proinflammatory cytokines. Blood 2013, 121, 2647–2658. [Google Scholar] [CrossRef] [PubMed][Green Version]
  24. Schirmer, L.; Rothhammer, V.; Hemmer, B.; Korn, T. Enriched CD161highCCR6+γδ T Cells in the Cerebrospinal Fluid of Patients With Multiple Sclerosis. JAMA Neurol. 2013, 70, 345–351. [Google Scholar] [CrossRef][Green Version]
  25. Kouli, A.; Jensen, M.; Papastavrou, V.; Scott, K.M.; Kolenda, C.; Parker, C.; Solim, I.H.; Camacho, M.; Martin-Ruiz, C.; Williams-Gray, C.H. T lymphocyte senescence is attenuated in Parkinson’s disease. J. Neuroinflamm. 2021, 18, 228. [Google Scholar] [CrossRef]
  26. Billerbeck, E.; Kang, Y.-H.; Walker, L.; Lockstone, H.; Grafmueller, S.; Fleming, V.; Flint, J.; Willberg, C.B.; Bengsch, B.; Seigel, B.; et al. Analysis of CD161 expression on human CD8+ T cells defines a distinct functional subset with tissue-homing properties. Proc. Natl. Acad. Sci. USA 2010, 107, 3006–3011. [Google Scholar] [CrossRef][Green Version]
  27. Sallusto, F.; Impellizzieri, D.; Basso, C.; Laroni, A.; Uccelli, A.; Lanzavecchia, A.; Engelhardt, B. T-cell trafficking in the central nervous system. Immunol. Rev. 2012, 248, 216–227. [Google Scholar] [CrossRef]
  28. Reboldi, A.; Coisne, C.; Baumjohann, D.; Benvenuto, F.; Bottinelli, D.; Lira, S.A.; Uccelli, A.; Lanzavecchia, A.; Engelhardt, B.; Sallusto, F. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat. Immunol. 2009, 10, 514–523. [Google Scholar] [CrossRef]
  29. Yan, Z.; Yang, W.; Wei, H.; Dean, M.N.; Standaert, D.G.; Cutter, G.R.; Benveniste, E.N.; Qin, H. Dysregulation of the Adaptive Immune System in Patients With Early-Stage Parkinson Disease. Neurol. Neuroimmunol. Neuroinflamm. 2021, 8, e1036. [Google Scholar] [CrossRef]
  30. Subramanian, S.; Ayala, P.; Wadsworth, T.L.; Harris, C.J.; Vandenbark, A.A.; Quinn, J.F.; Offner, H. CCR6: A Biomarker for Alzheimer’s-like Disease in a Triple Transgenic Mouse Model. J. Alzheimer’s Dis. 2010, 22, 619–629. [Google Scholar] [CrossRef][Green Version]
  31. Bulati, M.; Buffa, S.; Martorana, A.; Gervasi, F.; Camarda, C.; Azzarello, D.M.; Monastero, R.; Caruso, C.; Colonna-Romano, G. Double Negative (IgG+IgD−CD27−) B Cells are Increased in a Cohort of Moderate-Severe Alzheimer’s Disease Patients and Show a Pro-Inflammatory Trafficking Receptor Phenotype. J. Alzheimer’s Dis. 2015, 44, 1241–1251. [Google Scholar] [CrossRef] [PubMed]
  32. Goldeck, D.; Larbi, A.; Pellicanó, M.; Alam, I.; Zerr, I.; Schmidt, C.; Fulop, T.; Pawelec, G. Enhanced Chemokine Receptor Expression on Leukocytes of Patients with Alzheimer’s Disease. PLoS ONE 2013, 8, e66664. [Google Scholar] [CrossRef] [PubMed][Green Version]
  33. Man, S.-M.; Ma, Y.-R.; Shang, D.-S.; Zhao, W.-D.; Li, B.; Guo, D.-W.; Fang, W.-G.; Zhu, L.; Chen, Y.-H. Peripheral T cells overexpress MIP-1α to enhance its transendothelial migration in Alzheimer’s disease. Neurobiol. Aging 2007, 28, 485–496. [Google Scholar] [CrossRef] [PubMed]
  34. Ubogu, E.E.; Callahan, M.K.; Tucky, B.H.; Ransohoff, R.M. CCR5 expression on monocytes and T cells: Modulation by transmigration across the blood–brain barrier in vitro. Cell. Immunol. 2006, 243, 19–29. [Google Scholar] [CrossRef] [PubMed][Green Version]
  35. Li, M.; Shang, D.-S.; Zhao, W.-D.; Tian, L.; Li, B.; Fang, W.-G.; Zhu, L.; Man, S.-M.; Chen, Y.-H. Amyloid β Interaction with Receptor for Advanced Glycation End Products Up-Regulates Brain Endothelial CCR5 Expression and Promotes T Cells Crossing the Blood-Brain Barrier. J. Immunol. 2009, 182, 5778–5788. [Google Scholar] [CrossRef] [PubMed][Green Version]
  36. Hwang, C.J.; Park, M.H.; Hwang, J.Y.; Kim, J.H.; Yun, N.Y.; Oh, S.Y.; Song, J.K.; Seo, H.O.; Kim, Y.-B.; Oh, K.-W.; et al. CCR5 deficiency accelerates lipopolysaccharide-induced astrogliosis, amyloid-beta deposit and impaired memory function. Oncotarget 2016, 7, 11984–11999. [Google Scholar] [CrossRef][Green Version]
  37. Van De Berg, P.J.E.J.; Yong, S.-L.; Remmerswaal, E.; van Lier, R.; Berge, I.J.M.T. Cytomegalovirus-Induced Effector T Cells Cause Endothelial Cell Damage. Clin. Vaccine Immunol. 2012, 19, 772–779. [Google Scholar] [CrossRef][Green Version]
  38. Liu, C.; Cui, G.; Zhu, M.; Kang, X.; Guo, H. Neuroinflammation in Alzheimer’s disease: Chemokines produced by astrocytes and chemokine receptors. Int. J. Clin. Exp. Pathol. 2014, 7, 8342–8355. [Google Scholar]
  39. Reale, M.; Iarlori, C.; Thomas, A.; Gambi, D.; Perfetti, B.; Di Nicola, M.; Onofrj, M. Peripheral cytokines profile in Parkinson’s disease. Brain Behav. Immun. 2009, 23, 55–63. [Google Scholar] [CrossRef]
  40. Galiano-Landeira, J.; Torra, A.; Vila, M.; Bové, J. CD8 T cell nigral infiltration precedes synucleinopathy in early stages of Parkinson’s disease. Brain 2020, 143, 3717–3733. [Google Scholar] [CrossRef]
  41. Suvas, S.; Azkur, A.K.; Rouse, B.T. Qa-1b and CD94-NKG2a interaction regulate cytolytic activity of herpes simplex virus-specific memory CD8+ T cells in the latently infected trigeminal ganglia. J. Immunol. 2006, 176, 1703–1711. [Google Scholar] [CrossRef] [PubMed][Green Version]
  42. Gumá, M.; Busch, L.K.; Salazar-Fontana, L.I.; Bellosillo, B.; Morte, C.; García, P.; López-Botet, M. The CD94/NKG2C killer lectin-like receptor constitutes an alternative activation pathway for a subset of CD8+ T cells. Eur. J. Immunol. 2005, 35, 2071–2080. [Google Scholar] [CrossRef] [PubMed]
  43. van Bijnen, S.T.; Withaar, M.; Preijers, F.; van der Meer, A.; de Witte, T.; Muus, P.; Dolstra, H. T cells expressing the activating NK-cell receptors KIR2DS4, NKG2C and NKG2D are elevated in paroxysmal nocturnal hemoglobinuria and cytotoxic toward hematopoietic progenitor cell lines. Exp. Hematol. 2011, 39, 751–762.e3. [Google Scholar] [CrossRef] [PubMed]
  44. Appel, S.H. CD4+ T cells mediate cytotoxicity in neurodegenerative diseases. J. Clin. Investig. 2009, 119, 13–15. [Google Scholar] [CrossRef] [PubMed]
  45. Groh, V.; Brühl, A.; El-Gabalawy, H.; Nelson, J.L.; Spies, T. Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. Proc. Natl. Acad. Sci. USA 2003, 100, 9452–9457. [Google Scholar] [CrossRef] [PubMed][Green Version]
  46. Roberts, T.K.; Eugenin, E.A.; Lopez, L.; Romero, I.A.; Weksler, B.B.; Couraud, P.-O.; Berman, J.W. CCL2 disrupts the adherens junction: Implications for neuroinflammation. Lab. Investig. 2012, 92, 1213–1233. [Google Scholar] [CrossRef][Green Version]
  47. Zecca, L.; Wilms, H.; Geick, S.; Claasen, J.-H.; Brandenburg, L.-O.; Holzknecht, C.; Panizza, M.L.; Zucca, F.A.; Deuschl, G.; Sievers, J.; et al. Human neuromelanin induces neuroinflammation and neurodegeneration in the rat substantia nigra: Implications for Parkinson’s disease. Acta Neuropathol. 2008, 116, 47–55. [Google Scholar] [CrossRef]
  48. Rentzos, M.; Nikolaou, C.; Andreadou, E.; Paraskevas, G.P.; Rombos, A.; Zoga, M.; Tsoutsou, A.; Boufidou, F.; Kapaki, E.; Vassilopoulos, D. Circulating interleukin-15 and RANTES chemokine in Parkinson’s disease. Acta Neurol. Scand. 2007, 116, 374–379. [Google Scholar] [CrossRef]
  49. Gangemi, S.; Basile, G.; Merendino, R.A.; Epifanio, A.; Di Pasquale, G.; Ferlazzo, B.; Nicita-Mauro, V.; Morgante, L. Effect of levodopa on interleukin-15 and RANTES circulating levels in patients affected by Parkinson’s disease. Mediat. Inflamm. 2003, 12, 251–253. [Google Scholar] [CrossRef][Green Version]
  50. Tang, P.; Chong, L.; Li, X.; Liu, Y.; Liu, P.; Hou, C.; Li, R. Correlation between Serum RANTES Levels and the Severity of Parkinson’s Disease. Oxidative Med. Cell. Longev. 2014, 2014, 208408. [Google Scholar] [CrossRef][Green Version]
  51. Reale, M.; Greig, N.H.; Kamal, M.A. Peripheral chemo-cytokine profiles in Alzheimer’s and Parkinson’s diseases. Mini Rev. Med. Chem. 2009, 9, 1229–1241. [Google Scholar] [CrossRef] [PubMed]
  52. Reale, M.; Iarlori, C.; Feliciani, C.; Gambi, D. Peripheral chemokine receptors, their ligands, cytokines and Alzheimer’s disease. J. Alzheimer’s Dis. 2008, 14, 147–159. [Google Scholar] [CrossRef] [PubMed]
  53. Dhanwani, R.; Lima-Junior, J.R.; Sethi, A.; Pham, J.; Williams, G.; Frazier, A.; Xu, Y.; Amara, A.W.; Standaert, D.G.; Goldman, J.G.; et al. Transcriptional analysis of peripheral memory T cells reveals Parkinson’s disease-specific gene signatures. npj Park. Dis. 2022, 8, 30. [Google Scholar] [CrossRef] [PubMed]
  54. Fu, J.; Huang, Y.; Bao, T.; Liu, C.; Liu, X.; Chen, X. The role of Th17 cells/IL-17A in AD, PD, ALS and the strategic therapy targeting on IL-17A. J. Neuroinflamm. 2022, 19, 98. [Google Scholar] [CrossRef]
  55. Cao, J.-J.; Li, K.-S.; Shen, Y.-Q. Activated Immune Cells in Parkinson’s Disease. J. Neuroimmune Pharmacol. 2011, 6, 323–329. [Google Scholar] [CrossRef]
  56. Cardona, S.M.; Garcia, J.A.; Cardona, A.E. The Fine Balance of Chemokines During Disease: Trafficking, Inflammation, and Homeostasis. Methods Mol. Biol. 2013, 1013, 1–16. [Google Scholar] [CrossRef][Green Version]
  57. Sallusto, F.; Lenig, D.; Mackay, C.; Lanzavecchia, A. Flexible Programs of Chemokine Receptor Expression on Human Polarized T Helper 1 and 2 Lymphocytes. J. Exp. Med. 1998, 187, 875–883. [Google Scholar] [CrossRef]
  58. Martin-Blondel, G.; Brassat, D.; Bauer, J.; Lassmann, H.; Liblau, R. CCR5 blockade for neuroinflammatory diseases—Beyond control of HIV. Nat. Rev. Neurol. 2016, 12, 95–105. [Google Scholar] [CrossRef]
  59. Choi, D.-Y.; Lee, M.K.; Hong, J.T. Lack of CCR5 modifies glial phenotypes and population of the nigral dopaminergic neurons, but not MPTP-induced dopaminergic neurodegeneration. Neurobiol. Dis. 2013, 49, 159–168. [Google Scholar] [CrossRef]
  60. Nissen, S.K.; Farmen, K.; Carstensen, M.; Schulte, C.; Goldeck, D.; Brockmann, K.; Romero-Ramos, M. Changes in CD163+, CD11b+, and CCR2+ peripheral monocytes relate to Parkinson’s disease and cognition. Brain Behav. Immun. 2022, 101, 182–193. [Google Scholar] [CrossRef]
  61. Cen, L.; Yang, C.; Huang, S.; Zhou, M.; Tang, X.; Li, K.; Guo, W.; Wu, Z.; Mo, M.; Xiao, Y.; et al. Peripheral Lymphocyte Subsets as a Marker of Parkinson’s Disease in a Chinese Population. Neurosci. Bull. 2017, 33, 493–500. [Google Scholar] [CrossRef] [PubMed]
  62. Zhu, B.; Yin, D.; Zhao, H.; Zhang, L. The immunology of Parkinson’s disease. Semin. Immunopathol. 2022, 44, 659–672. [Google Scholar] [CrossRef] [PubMed]
  63. Tian, J.; Dai, S.-B.; Jiang, S.-S.; Yang, W.-Y.; Yan, Y.-Q.; Lin, Z.-H.; Dong, J.-X.; Liu, Y.; Zheng, R.; Chen, Y.; et al. Specific immune status in Parkinson’s disease at different ages of onset. NPJ Park. Dis. 2022, 8, 5. [Google Scholar] [CrossRef] [PubMed]
Figure 1. CD8+/− T-cells. Frequencies of CD8+ T-cells expressing the receptors NKG2A (a) and NKG2C (b) and frequencies of CD8− T-cells expressing the receptor NKG2C (c) relative to CD3+ cells. Median fluorescence intensities of receptor NKG2D on CD8+ T-cells (d). Frequencies of CD4-CD56+ NKT-cells expressing CCR5 (e). p-values were calculated using Mann–Whitney U Tests comparing PD patients to controls. Outliers are presented as circles. * p < 0.05.
Figure 1. CD8+/− T-cells. Frequencies of CD8+ T-cells expressing the receptors NKG2A (a) and NKG2C (b) and frequencies of CD8− T-cells expressing the receptor NKG2C (c) relative to CD3+ cells. Median fluorescence intensities of receptor NKG2D on CD8+ T-cells (d). Frequencies of CD4-CD56+ NKT-cells expressing CCR5 (e). p-values were calculated using Mann–Whitney U Tests comparing PD patients to controls. Outliers are presented as circles. * p < 0.05.
Jal 03 00001 g001
Table 1. Frequencies of NK-cells in PD and expression of CCR5 and CXCR2.
Table 1. Frequencies of NK-cells in PD and expression of CCR5 and CXCR2.
MarkersCellsPD Patients % (Median (Range))Control %
(Median (Range))
p Values 1
CD3-CD56+ 2Total NK-cells5.27 (0.51–11.52)5.42 (2.25–14.54)0.77
CD3-CD56highCD16low 2Immature NK-cells0.30 (0.06–0.70)0.24 (0.09–0.98)0.52
CD3-CD56lowCD16high 2Mature NK-cells4.72 (0.33–10.68)4.93 (1.55–13.92)0.67
CD3-CD56lowCD16high CD57+ 2Late stage mature NK-cells2.44 (0.27–5.77)3.00 (0.71–11.15)0.20
CD3-CD56lowCD16high CD161+ 2CD161+ mature NK-cells3.89 (0.28–9.01)4.53 (1.19–12.51)0.57
CD3-CD56lowCD16high CCR5+ 3CCR5 expressing mature NK-cells0.10 (0.04–1.00)0.08 (0.02–0.58)0.44
CD3-CD56lowCD16high CCR5 median 4CCR5 expressing mature NK-cells899 (232–543)347 (202–541)0.37
CD3-CD56lowCD16high CXCR2 median 4CXCR2 expressing mature NK-cells1008 (717–1585)382 (538–1998)0.15
1p values were calculated using Mann–Whitney U Tests; 2 analysis based on % of CD45+, 3 analysis based on % of CD3+, 4 analysis based on median fluorescence intensities.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Goldeck, D.; Schulte, C.; Teixeira dos Santos, M.C.; Scheller, D.; Öttinger, L.; Pawelec, G.; Deuschle, C.; Berg, D.; Nogueira da Costa, A.; Maetzler, W. Higher Frequencies of T-Cells Expressing NK-Cell Markers and Chemokine Receptors in Parkinson’s Disease. J. Ageing Longev. 2023, 3, 1-10.

AMA Style

Goldeck D, Schulte C, Teixeira dos Santos MC, Scheller D, Öttinger L, Pawelec G, Deuschle C, Berg D, Nogueira da Costa A, Maetzler W. Higher Frequencies of T-Cells Expressing NK-Cell Markers and Chemokine Receptors in Parkinson’s Disease. Journal of Ageing and Longevity. 2023; 3(1):1-10.

Chicago/Turabian Style

Goldeck, David, Claudia Schulte, Marcia Cristina Teixeira dos Santos, Dieter Scheller, Lilly Öttinger, Graham Pawelec, Christian Deuschle, Daniela Berg, Andre Nogueira da Costa, and Walter Maetzler. 2023. "Higher Frequencies of T-Cells Expressing NK-Cell Markers and Chemokine Receptors in Parkinson’s Disease" Journal of Ageing and Longevity 3, no. 1: 1-10.

Article Metrics

Back to TopTop