PD is the second most common neurodegenerative disease after AD. PD is characterised by the loss of 50 to 70% of dopaminergic neurons located in the substantia nigra pars compacta (SN
pc). The progressive degeneration of dopaminergic fibres in the brain results in prominent motor symptoms, such as bradykinesia, tremors, rigidity and postural instability. Although studied less in PD than in MS, the fundamental participation of T-cells has also been described in PD. An altered frequency of peripheral CD4
+ T-cells has been described in blood samples obtained from PD patients [
47],[
48]. Moreover, CD4
+ and CD8
+ T-cells that infiltrated into the brain parenchyma have been found in
post-mortem samples obtained from PD patients [
49],[
50], as well as in animal models using mice [
50],[
51] and rats [
52]. Recent studies carried out with T-cell receptor (TCR)-β-chain-deficient mice, SCID mice and recombination-activating-gen-1 (RAG1) knockout (RAG1KO) mice demonstrated that T-cell deficiency results in a strong attenuation of dopaminergic neurodegeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD [
50],[
53]. This reveals that T-cells are not only relevant, but are also required for neurodegeneration in PD. Additional experiments have shown that although CD8
+ T-cell deficiency is negligible, the participation of CD4
+ T-cells is fundamental for promoting the neurodegeneration of dopaminergic neurons in the SN
pc of mice with PD [
50]. These studies support the involvement of pathogenic CD4
+ T-cell populations, which would induce the acquisition of an M1-like pro-inflammatory phenotype by the microglia, which is characterised by the secretion of inflammatory factors such as TNF-α, IL-1β, glutamate and superoxide [
14],[
54]. Supporting the pivotal role of CD4
+ T-cells potentiating microglial activation and favouring neurodegeneration in PD, it has recently been reported that a deficiency of class II major histocompatibility complex (MHC) results in attenuation of both microgliosis and loss of dopaminergic neurons in a mouse model of PD [
55]. Experiments addressing the phenotype of pathogenic CD4
+ T-cells involved in PD have shown that both Th1 and Th17 autoreactive cells are important for the promotion of neuronal loss [
26]. Addressing the molecular mechanisms involved in CD4
+ T-cell-mediated loss of dopaminergic neurons in PD, a study has shown that the participation of Fas-FasL interactions seems to contribute to the neurodegenerative process [
50]. Importantly, we have recently demonstrated that dopamine receptor D3 (D3R), expressed in CD4
+ T-cells, is fundamental in inducing the loss of dopaminergic neurons in the SN
pc of a PD mouse model [
17]. In this regard, we and others have reported that D3R-deficient (D3RKO) mice are resistant to MPTP-induced PD [
17],[
56]. Interestingly, when wild type (WT) CD4
+ T-cells were transferred to D3RKO mice, the animals acquired the capability to respond to MPTP-induced neurodegeneration. On the other hand, RAG1KO mice, which are devoid of T-cells and are resistant to MPTP-induced PD, acquire the capability to respond to MPTP-induced neurodegeneration when WT CD4
+ T-cells were transferred, but not when D3RKO CD4
+ T-cells were transferred [
17]. Notably, our data indicate that the stimulation of D3R expressed on CD4
+ T-cells favours the acquisition of Th1 inflammatory cells, thus indicating the crucial importance of this pathogenic phenotype in the CD4
+ T-cells immune response that is involved in PD [
17]. In this regard, we observed that WT, but not D3RKO, CD4
+ T-cells infiltrating the SN
pc during MPTP-induced PD produced high levels of IFN-γ and TNF-α, which are two cytokines that act synergistically in microglia, promoting the inflammatory M1-like phenotype [
57]. Thus, these findings point towards the important role of CNS-derived dopamine in the regulation of T-cell-mediated immunity during neuroinflammation. Conversely, other T-cell subsets, such as Tregs and Th2, could contribute to microglial acquisition of an M2-like anti-inflammatory phenotype, which release neurotrophic factors, including IGF-1, promoting neuronal protection [
14],[
26]. Indeed, it has been demonstrated that Tregs elicit neuroprotection for dopaminergic neurons of SN
pc in MPTP-induced PD in mice [
26],[
58]. Further analyses have shown that these Tregs cells act directly on activated M1-like microglial cells, attenuating migration, phagocytosis and the production of neurotoxic factors [
58],[
59].
In vitro experiments have shown that Tregs-mediated inhibition of M1-like microglia functions occurred through the suppression of NF-κB activation and required not only soluble mediators from Tregs, but also cell-cell contacts with microglial cells [
59]. Another group of studies have also shown evidence of the neuroprotective role of Tregs in PD. In these studies, copolymer-1 was used as an immunogen, which is a potent inducer of encephalitogenic Tregs [
60]. It has been shown that adoptive transference of CD4
+ T-cells isolated from mice, immunised with copolymer-1, attenuates the neurodegeneration of dopaminergic neurons in SN
pc of mice with MPTP-induced PD [
61]. On the other hand, Reynolds
et al. found that Th2 cells, which are specific against CNS antigens involved in PD, do not play a relevant role, exacerbating or attenuating neurodegeneration in MPTP-induced PD [
26]. Other encephalitogenic T-cell subsets described as playing important inflammatory or anti-inflammatory roles in MS have not yet been studied in PD. Thus, future efforts are necessary to elucidate the participation of anti-inflammatory CD8
+ T-cell subsets, inflammatory γδT-cells and GM-CSF-producer T-helper cells in the physiopathology of PD. An integrative summary of the role of T-cells in the neurodegenerative process associated with PD is shown in Figure
1.