Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease and the fastest growing neurological disorder in world, with 12.9 million patients predicted worldwide by 2040 [1]. The hallmark pathological features of PD include the loss of dopaminergic (DA) neurons in the midbrain substantia nigra pars compacta (SNpc) and the formation of Lewy bodies, which are composed of alpha-synuclein (α-syn) [2]. Patients with PD present with motor symptoms, including bradykinesia, stiffness, resting tremor, and postural instability, as well as a variety of non-motor symptoms, such as depression, autonomic disorders, and cognitive impairment, which lead to a dramatic decline in the quality of life of patients and increase the financial burden on patients and the healthcare system [3,4,5]. The occurrence of PD is associated with various risk factors, including gene mutations [6], environmental risks [7], gut microbiota disturbances [8] and unhealthy lifestyles [9]. Recent studies have shown that the dysregulation of the immune system also plays a crucial role in the pathogenesis of PD [10,11,12].

Specific factors, such as viruses, heavy metals, and some severe brain injuries, drive the activation of neuroinflammation [13]. Neuroinflammation is an inflammatory response of the central nervous system (CNS) in response to factors that interfere with homeostasis. This response entails a concerted effort from resident glial cells in the CNS, such as microglia, oligodendrocytes, and astrocytes, alongside non-glial resident bone marrow cells including macrophages and dendritic cells (DCs) and peripheral white blood cells [14]. Recent evidence has revealed that neuroinflammation plays an important role in the occurrence and development of neurodegenerative diseases, such as PD, Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD) [15].

Many studies have shown that the proportion of different subsets of T cells changes significantly in the peripheral blood of PD patients. Wang et al. compared the proportion of CD4+ T cells and CD8+ T cells in the peripheral blood of PD patients and healthy controls and found that the proportion of CD8+ T cells in PD patients increased significantly compared with healthy controls, while the proportion of CD4+ T cells decreased significantly. This resulted in a significantly lower overall CD4/CD8 ratio in PD patients, indicating that PD patients may have immune disorders [16]. However, Chen et al. found that the proportion of CD3+ T and CD4+ T cells in the peripheral blood of PD patients was higher than in healthy controls, while the proportion of CD8+ T cells did not change significantly, resulting in a significant increase in the CD4/CD8 ratio of PD patients [17]. Therefore, the proportion of T cells in the peripheral blood of PD patients is not consistent, which may be due to different PD samples [17].

Notably, Brochard et al.‘s study suggests that CD4+ T cells have a stronger correlation than CD8+ T cells in mouse models of PD. Specifically, the lacking of CD4+ but not CD8+ T cells in mice significantly reduced 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine-containing neurons (DNs) cell death in the SNpc [18]. Furthermore, Williams et al. observed that overexpression of α-syn enhanced the infiltration of both CD4+ and CD8+ T cells into the CNS parenchyma in mice [19]. Conversely, the knockout (KO) or pharmacological inhibition of T cells, particularly CD4+ T cells, protected against the loss of tyrosine hydroxylase-positive (TH+) neurons in the SNpc [19]. These findings suggest a potentially critical role of neuroinflammation, specifically CD4+ T cells, in the pathogenesis and progression of PD.

In this review, we systematically summarize the differentiation of different subsets of CD4+ T cells, focus on the mechanism of different subsets and their secreted cytokines in the development of PD, and finally elaborate the immunotherapy targeting CD4+ T cell for PD to provide further evidence for the diagnosis and treatment of PD.

Differentiation of CD4+ T cell subsets

T lymphocytes originate from the bone marrow, then migrate to the thymus for maturation, and ultimately export to the periphery, where they play important roles in the peripheral tissues and various lymphatic organs. Progenitor cells lacking CD4+ and CD8+ receptors in the bone marrow generate CD4+CD8+ double-positive (DP) thymocytes via T cell receptor (TCR) rearrangement. DP cells undergo selection to produce either CD4+ or CD8+ single-positive (SP) thymocytes, which subsequently enter the periphery as naïve T cells [20, 21]. Recognition of major histocompatibility complex class II (MHC-II) on antigen-presenting cells (APCs), such as DCs, is a prerequisite for activating CD4+ T cells. Subsequently, under the combined stimulation from TCR signaling, APCs, and cytokines, the naïve CD4+ T cells are fully activated and differentiated into distinct cell subsets, including T helper (Th) 1 cells, Th2 cells, Th9 cells, Th17 cells, regulatory T cells (Tregs) and T follicular helper (Tfh) cells [22, 23]. Notably, the expression of specific transcription factors is required for T cell differentiation (Fig. 1) [24].

Fig. 1
figure 1

Cytokines and master transcription factors in CD4+ T cell subsets. Under the regulation of specific cytokines, the naïve CD4+ T cells differentiate into different cell subsets, which play an important role in the immune response. Key transcription factors such as T-bet, GATA-3, PU.1, ROR-γt, FOXP3, and Bcl-6 are also essential for the differentiation and maintenance of CD4+ T cells. Th1 cells mainly release cytokines such as IL-2, TNF-α and IFN-γ, while Th2 cells secrete cytokines such as IL-4, IL-5 and IL-13. Th9 cells mainly secrete IL-9. Th17 cells perform pro-inflammatory function by releasing IL-17, IL-21, and IL-22. In contrast, the anti-inflammatory function of Tregs cells is mainly mediated by cytokines such as IL-10, IL-35 and TGF-β. IL-4, IL-10, and IFN-γ are produced by Tfh cells

Full size image

Th1 cells

Th1 cells primarily mediate immune responses against extracellular pathogens [25]. Interleukin 12 (IL-12) and interferon gamma (IFN-γ) are key cytokines that initiate the differentiation of CD4+ T cells into Th1 cells [26]. APCs, upon activation, release high levels of IL-12, which stimulates natural killer (NK) cells to produce IFN-γ [27]. In turn, IL-12 secreted by APCs and IFN-γ produced by NK cells activate the transcription factors signal transducer and activator of transcription 4 (STAT4) and STAT1, respectively, which further induce T-box expressed in T cells (T-bet) expression, thereby promoting Th1 cell polarization [28, 29] (Fig. 2a). In addition, IL-18 and IL-27 also promote Th1 differentiation and the production of IFN-γ [30,31,32]. T-bet, the main transcription factor of Th1 cells, is specifically expressed in Th1 cell subset and induces the production of IFN-γ, which plays a decisive role in Th1 cell differentiation [33]. T-bet also plays important roles in Th1 cell polarization by regulating the expressions of other transcription factors. For example, T-bet induces Runt-associated transcription factor 3 (RUNX3) expression, which then co-binds to the IFN-γ promoter to promote Th1 cell differentiation [34, 35].

Fig. 2
figure 2

The regulation networks of CD4+ T cell subsets. IL-12 and IFN-γ are key cytokines that initiate the differentiation of CD4+ T cells into Th1 cells. They activate the transcription factors STAT4 and STAT1, respectively, and then induce the expression of T-bet and the polarization of Th1 cells (a). The main transcription factor involved in Th2 subset differentiation is GATA-3, which is regulated by IL4-induced STAT6 (b). Th9 cells are derived from naïve CD4+ T cells induced by TGF-β and IL-4 and mainly secrete IL-9. In addition, cytokines such as IL-1, IL-25 and IL-33 also promote the differentiation of Th9 cells and the production of IL-9. Downstream transcription factors of IL-4 and TGF-β, such as STAT6, IRF4, SMAD3, etc., are also necessary for Th9 cell differentiation (c). IL-6 and TGF-β are the main cytokines involved in Th17 cell differentiation, which promote the transcription of ROR-γt by up-regulating the expression of STAT3 and SMAD. In addition, Th17 cell differentiation is also regulated by IL-23 and IL-1β (d). FOXP3 and Bcl-6 are transcription factors that play dominant roles in the differentiation of Tregs (e) and Tfh cells (f), respectively, and their expression is regulated by cytokines such as IL-2 and TGF-β, and IL-6, IL-21 and IL-27

Full size image

Th2 cells

Th2 cells primarily mediate host defense against large extracellular pathogens, including parasites [25]. IL-4 and IL-2 are the main regulators of Th2 differentiation. The main transcription factor involved in Th2 subset differentiation is GATA binding protein 3 (GATA-3), which is regulated by IL4-induced STAT6 [36, 37]. GATA-3 activates the expression of Th2 cytokines (IL-4, IL-5, and IL-13) by directly binding to different regions of gene loci, thereby promoting Th2 cell differentiation [38] (Fig. 2b). Interestingly, although IL-4 and IL-2 are required for Th2 cell differentiation in vitro, normal Th2 cell development is still observed in IL-4 and STAT6-deficient mice, suggesting that Th2 cells can differentiate independently on IL-4-STAT6 signaling in vivo [39]. Additionally, GATA-3 also inhibits the expression of transcription factors related to other T cell subsets, such as STAT4, T-bet and retinoic acid receptor-related orphan receptor gamma t (ROR-γt) [38, 40,41,42,43,44,45], and thus inhibits differentiation into other cell subsets.

Th9 cells

Th9 cells are a new subset of CD4+ T cells differentiated from naïve CD4+ T induced by transforming growth factor β (TGF-β) and IL-4, and mainly secrete IL-9 [46]. Studies have shown that Th9 cells play an important role in the immune response to diseases such as autoimmune diseases [47, 48] and cancers [49, 50]. IL-4 is the key cytokine involved in the differentiation of Th9 cells. Interestingly, IL-4 alone induces Th2 differentiation, but in the presence of TGF-β, it converts the Th2 cell phenotype to the Th9 cell phenotype [51]. Other cytokines, including IL-1 [52], IL-2 [53], IL-10 [54], IL-21 [55], IL-25 [56], IL-33 [57], and tumor necrosis factor-α (TNF-α) [58], have also been shown to promote the differentiation of Th9 cells and the production of IL-9. However, IFN-γ and IL-27 have been found to inhibit the production of IL-9 [59]. Downstream transcription factors of IL-4 and TGF-β, such as STAT6 [60], GATA-3 [61, 62], interferon regulatory factor 4 (IRF4) [63], and small mother against decapentaplegic (SMAD)3 [64], are also required for Th9 cell differentiation. Additionally, TGF-β induces the expression of the signature transcription factor PU.1 in Th9 cells, which promotes their differentiation by interfering with GATA-3 expression [65] or affecting chromatin modification through binding to the IL-9 promoter [66], as well as inhibits Th2 cells differentiation (Fig. 2c) [67].

Th17 cells

Th17 cells are a newly discovered CD4+ T cell subset that mainly mediate the host’s immune response to extracellular bacterial and fungal infections through the secretion of IL-17 and other inflammatory cytokines [68,69,70,71,72]. IL-6 and TGF-β are the main cytokines involved in Th17 cell differentiation and induce mouse naïve T cells to differentiate into Th17 cells in vitro and in vivo [73,74,75]. In the absence of IL-6, IL-21 is combined with TGF-β to induce the expression of ROR-γt during T cell differentiation, suggesting that IL-21 combined with TGF-β can induce Th17 cells differentiation independently on IL-6, although the efficiency is lower than that of the combination of IL-6 and TGF-β [76]. In addition, the differentiation of Th17 cells is also regulated by IL-23 [74] and IL-1β [77] (Fig. 2d).

As the most important transcription factor of Th17 cells, ROR-γt induces IL-17A/F expression and Th17 cells differentiation in antigen-stimulated naïve CD4+ T cells [78]. The expression of ROR-γt is positively regulated by IL-6/21/23, TGF-β, and some transcription factors, such as STAT3, IRF4, eomesodermin (Eomes), RUNX1, c-Rel, and induces the differentiation of naïve CD4+ T cells into Th17 cells [79]. Yang et al. also found that ROR-γt and RORα, another orphan nuclear receptor, co-expression synergistically promoted Th17 differentiation in vitro [80].

Tregs

Tregs play an important role in preventing autoimmune diseases and maintaining immune homeostasis as inhibitors of inflammatory response [81, 82]. Tregs are induced in vitro by naïve CD4+ T cells in the presence of specific factors such as TGF-β and IL-2 [83]. FOXP3 is a transcription factor that plays a dominant role in the differentiation of Tregs. Studies have shown that FOXP3 locus contains multiple conserved regulatory sequences [84] of many factors, such as STAT5 [85], SMADs [86], c-Rel [87], special AT-rich sequence-binding protein 1 (SATB1) [88], NFAT [89] and nuclear receptor 4 A (NR4A) [90], which bind to FOXP3 promoter or other regulatory regions to promote its transcription and induce the differentiation of Tregs (Fig. 2e). In addition, cytokines, especially IL-7 [91] and IL-15 [92], and other transcription factors, such as RUNX1 [93], FOXO1 [94] and Helios [95], also play a very important role in the differentiation and maintenance of Tregs.

Tfh cells

Tfh cells are a subset of CD4+ T cells first identified in human tonsil [96, 97], which help the formation of germinal centres (GCs), and promote the generation of high-affinity antibodies and the development of memory B cells [98,99,100]. Tfh cells play an important role in allergic reactions [101], systemic autoimmune diseases [102, 103] and chronic inflammation [104].

Like other T cell subsets, Tfh cell differentiation is also regulated by a variety of cytokines and transcription factors [98, 105, 106]. Briefly, cytokines such as IL-6 [107, 108], IL-12 [109], IL-21 [110], and IL-27 [111] promote Tfh cell differentiation, while IL-2 [112], IL-10 [113], and programmed death 1 (PD-1) [114] inhibit Tfh cell differentiation. B cell lymphoma 6 (Bcl-6) is a key transcription factor regulating Tfh cell differentiation, and it is crucial for the expression of Tfh cell-related factors and the development of Tfh cells [115, 116]. Transcription factors such as STAT1/3/4 [107, 117, 118], IRF4 [119] and basic leucine zipper transcription factor (BATF) [120] also play an active role in promoting the expression of Bcl-6 and the differentiation of Tfh cells (Fig. 2f).

CD4+ T cells and PD

The blood-brain barrier (BBB) is an important tissue to maintain the balance of the brain microenvironment, which can effectively prevent peripheral immune cells and other neurotoxic substances from entering the brain from the blood [121]. Therefore, CNS was once thought to be an “immunologically privileged” site where surrounding immune cells could not or rarely enter [122]. However, studies have shown that dysregulation of neuroinflammation disrupts the integrity of the BBB, which provides the possibility for peripheral immune cells to infiltrate the brain parenchyma [123]. As expected, increasing evidence proves that infiltrating T cells and inflammatory cytokines existed in the post-mortem brain tissues of PD patients and PD animal models, implicating T lymphocytes immune response happened in PD [124,125,126].

Brochard et al. [18] found that in a mouse model of PD, CD8+ and CD4+ T cells but not B cells invaded the brain. Further studies found that mice lacking CD4+ T cells attenuated MPTP-induced DA neuronal death, but not mice lacking CD8+ T cell. These results suggest that CD4+ T cells play a more important role in the development of PD. Similarly, many studies have shown disturbances in the peripheral immune cells and brain parenchyma of PD patients with CD4+ T cell subsets [17, 18, 127, 128]. Magistrelli et al. also found that peripheral CD4+ T cells were associated with cognitive dysfunction in patients with PD. Patients with cognitive impairment had more circulating CD4+ T cells than patients with normal cognitive function [129]. During the pathological development of PD, the abnormally accumulated α-syn binds to Toll-like receptors (TLR) to activate microglia, thereby inducing the release of pro-inflammatory cytokines (mainly IFN-γ and TNF-α) and promoting the differentiation of CD4+ T cells into Th1 and Th17 cells [130]. More importantly, a growing number of studies have shown that Th1 and Th17 aggravate the damage of DA neurons, while Th2 and Tregs have neuroprotective effects [131, 132]. Although there is currently no clear evidence to prove the function of Th9 cells and Tfh cells in PD, the cytokines secreted from these cells regulate neuronal survival. In addition, dysregulation of CD4+ T cell-related transcription factors is receiving attention since it is a special molecular feature of idiopathic rapid eye movement (REM) sleep behavior disorder patients and PD patients, and used to identify motor complications [133, 134]. Therefore, understanding the roles of CD4+ T cells and related cytokines in PD is crucial for the diagnosis and treatment of PD.

Th1 cell-associated cytokines in PD

Th1 cells are thought to have a pro-inflammatory phenotype and promote neuronal loss in neurodegenerative diseases such as PD. Compared with healthy controls, the number and frequency of Th1 cells in the peripheral blood of PD patients were significantly increased [135,136,137], and it was positively correlated with UPDRS-I score (Unified Parkinson’s Disease Rating Scale I score) and negatively correlated with MMSE score (Mini-Mental State Examination) [138, 139]. Kustrimovic et al. found that although the absolute number of Th1 cells in PD patients was similar to that in healthy controls, an increased proportion of Th1 cells was observed, which led to a Th1 bias [136]. As a result, Th1 cells significantly increased production of cytokines such as IFN-γ and TNF-α, which affect neuronal survival [140,141,142,143,144]. In PD animal models, increased Th1 cells were also found in the brain tissues of MPTP-treated PD mice, and adoptive transfer of Th1 cells increased neurodegeneration (Fig. 3) [145, 146].

IL-2

IL-2 is an immune cytokine that plays an important role in immune cell survival and anti-infection immunity. Benveniste and Saneto et al. first reported in 1986 that IL-2 inhibited the growth of glial cells, especially the proliferation and differentiation of oligodendrocytes [147, 148]. Later study found that IL-2 played a role by regulating the phagocytosis activity and the production of reactive oxygen species (ROS) in stimulated microglia-like cells [149]. In addition, IL-2 has been shown to be a potent regulator of DA neuron activity in the mesocortex limbic and mesocortex striatal systems, and plays a key role in inducing endogenous changes in the CNS and the homing of T cells into the brain [150, 151]. These results suggest that IL-2 plays an important role in neurological diseases, including PD.

Although a small number of studies are controversial [152, 153], more and more studies confirm that IL-2 level is significantly increased in peripheral blood [154,155,156,157] and cerebrospinal fluid (CSF) [158] of PD patients compared with healthy controls, and is negatively correlated with cognitive performance of early PD patients [159]. Similarly, IL-2 level was also found to be significantly increased in mouse PD models treated with MPTP or 6-hydroxydopamine (6-OHDA) [160,161,162]. Besides, α-syn overexpression also promoted the increase of IL-2 mRNA level in the cerebral cortex of mice [163].

TNF-α

In the CNS, TNF-α is mainly produced by glial cells and neurons in response to intracellular and extracellular stimuli and is considered to be the primary mediator of neuroinflammation [164]. TNF-α performs its biological function by binding to two cell surface receptors, TNFR1 (p55) and TNFR2 (p75). Although TNFR1 is expressed in most cell types, TNFR2 is mainly expressed by microglia and endothelial cells [165, 166].

A large number of studies have found that TNF-α is closely related to the pathological process of PD patients. The level of TNF-α in peripheral blood [157, 167, 168], CSF [158, 169] and brain [170, 171] of PD patients is significantly increased compared with healthy controls. Clinical studies have found that TNF-α (-308) gene polymorphisms increase the risk of PD [172]. In addition, the level of TNF-α in peripheral blood of PD patients is closely related to the severity of the symptoms, such as fatigue [173,174,175]. Therefore, TNF-α level may be an important biomarker for early diagnosis in PD patients.

TNF-α exacerbates the death of DA neurons in animal models of PD. Carvey et al. found that injection of TNF-α into the forebrain of mice resulted in the loss of DA neurons in the SN, providing direct evidence that TNF-α alone can induce the death of DA neurons [176]. In MPTP-treated PD mouse models, the number of activated microglia and pro-inflammatory cytokines were significantly reduced in TNF-α KO mice compared to WT mice, and MPTP-induced BBB destruction was also mitigated [177]. Similarly, in 6-OHDA-induced mouse or rat models, low expression of TNF-α in the SN significantly reduces the microglia activation and loss of SN neurons [178, 179]. In addition, mice lacking both TNFRs had a protective effect against MPTP-induced DA neuron loss [180, 181]. Using in vitro experiments, Takeuchi et al. found that TNF-α-induced neurotoxicity was caused by glutamate released from microglia [182]. Other studies have suggested that TNF-α released by activated microglia causes mitochondrial dysfunction, which in turn induces apoptosis of neurons or neural precursor cells [183, 184]. Interestingly, the accumulation of α-syn in PD patients is also thought to be associated with abnormal expression of TNF-α. Wang et al. demonstrated that a subtoxic dose of TNF-α impaired autophagy flux and disrupted α-syn degradation by reducing lysosomal acidification, leading to accumulation of α-syn in midbrain neurons [185]. Another study suggests that TNF-α-treated neurons promote the acquisition of a senescence-associated secretory phenotype (SASP), while α-syn secretion increases significantly in aging neurons [186].

Conversely, there is evidence that TNF-α also has a neuroprotective function. In 6-OHDA-treated PD mouse models, low levels of TNF-α reduced nigrostriatal neurodegeneration, while high levels increased neuronal loss [178]. This suggests that low levels of TNF-α may play a neuroprotective role in the development of PD. In addition, the timing of TNF-α expression, brain regions, and factors that stimulate TNF-α signaling may determine the role of TNF-α in neuroinflammation [187].

IFN-γ

IFN-γ is an important inflammatory cytokine, which mainly promotes the activation and proliferation of microglia, induces the expression of T-cell-related chemokines and plays an important role in microglia-mediated neurodegeneration [141, 188, 189]. Under pathological conditions, IFN-γ can enter the brain parenchyma through the BBB, then inhibits the proliferation of neural stem cells and precursor cells, finally induces the death of neurons [190, 191]. In addition, Hashioka et al. found that supernatants produced by IFN-γ-activated astrocytes reduced SH-SY5Y cell viability, suggesting that activated astrocytes generated neurotoxicity when stimulated by IFN-γ [192].

A large number of studies have found that IFN-γ in the peripheral blood of PD patients is significantly increased [156, 157, 193], however, there are also studies to prove that the level of IFN-γ in the peripheral blood of PD patients is unchanged or even decreased compared with healthy controls [153, 167, 194], and lower level of IFN-γ is associated with more severe tremor in PD patients [195]. Interestingly, unlike in patients with PD, IFN-γ level was significantly increased in multiple PD animal models [141, 161, 162, 168, 196,197,198]. In the CNS of IFN-γ transgenic mice, the proliferation of microglia and astrocytes was accelerated, accompanied by the degeneration of the SNpc and the reduction of TH+ neurons in the dense region of the SNpc. Moreover, the transgenic mice showed symptoms similar to frozen of gait, suggesting that IFN-γ has the potential to induce PD [199]. In MPTP-treated monkey PD models, microglia were extensively activated and IFN-γ immunoreactivity was observed, and expression level of IFN-γ was strongly correlated with motor impairment and DA cell death [141]. In addition, Xue et al. demonstrated that lipopolysaccharide (LPS) + IFN-γ treatment significantly increased the expression of IL-1β, TNF-α, and IL-6 in BV2 cells, and up-regulated the caspase3 level while down-regulated the Bcl-2 expression, suggesting that IFN-γ may induce neuronal apoptosis by increasing the expression of inflammatory factors [200]. Leucine-Rich Repeat Kinase 2 (LRRK2) is a PD-associated kinase, which mutations are significantly associated with an increased risk of PD [201]. It has been found that LRRK2 is induced by IFN-γ via extracellular signal-regulated kinase 5 (ERK5) [202], and their synergistic activation plays a potentially important role in inflammation and neurodegeneration in PD [203]. These studies suggest that the proinflammatory effects of IFN-γ play an important role in the pathological development of PD.

Th2-associated cytokines in PD

Contrary to Th1 cells, multiple studies have shown that Th2 cells are significantly reduced in PD patients, and the ratio of Th1/Th2 is significantly increased, and the ratio increases with the deterioration of the disease [135, 136, 138, 139, 204]. Studies have shown that α-syn plays an important role in the development and function of T lymphocytes. Shameli et al. found defective Th2 differentiation and significantly reduced IL-4 secretion in α-syn KO mice, which possibly due to the altered affinity of TCR interactions in the absence of α-syn [205]. The cytokines produced by Th2 cells (IL-4 and IL-13) are also involved in cognitive function by activating astrocytes, and these results are important for the prevention and treatment of neurodegenerative diseases such as PD (Fig. 3) [206,207,208].

Fig. 3
figure 3

The regulation mechanisms of Th1 and Th2 cells in PD. In PD animal models, inflammatory factors such as TNF-α, IFN-γ, and IL-2 secreted by Th1 cells enter the brain parenchyma through the BBB and promote neuroinflammatory response. TNF-α performs its biological function by binding to the cell surface receptor TNFR1. TNF-α significantly activates microglia and induces neuronal death. This neurotoxicity may be caused by glutamate released by microglia, mitochondrial dysfunction, and the acquisition of SASP. In addition, IFN-γ and IL-2 levels are also significantly elevated in PD models and have been shown to be effective regulators of DA neuronal activity. In contrast to Th1 cells, the secretion of IL-4 and other anti-inflammatory factors by Th2 cells in PD patients is significantly reduced. Microglia-derived IL-4 promotes neuroprotection by regulating the secretion of neuroprotective factors such as IGF-1

Full size image

IL-4/13

IL-4 and IL-13 are two cytokines mainly secreted by Th2 cells, in addition, Tfh and group 2 innate lymphoid cells (ILC2s) have also been found to be important sources of IL-4 and IL-13, respectively [209]. IL-4 and IL-13 genes are located in the same vicinity on chromosome 5, and they share 20–25% homology at amino acid level [210]. Additionally, IL-4 and IL-13 partially share a same receptor, the IL-13 receptor alpha 1 chain (IL-13Rα1) [211]. Therefore, they may have similar biological functions.

In most studies, IL-4 and IL-13 have been shown to have a neuroprotective effect on the CNS by reducing the inflammatory response. IL4 and IL-13 induced the death of microglia treated with neurotoxins such as LPS and ganglioside mixture (Gmix) in vitro, thereby increasing neuronal survival [212]. IL-13 promoted cognitive function by stimulating the production of brain-derived neurotrophic factors (BDNF) by primary astrocytes [208]. In a mouse model of permanent middle cerebral artery occlusion (pMCAo), IL-13 treatment significantly increased the M2-type microglia/macrophage ratio in ischemic areas of brain and the anti-inflammatory cytokines IL-6 and IL-10 levels in the plasma [213]. IL-13 also produced long-term neuroprotection in mice with transient middle cerebral artery occlusion (tMCAO) by inhibiting STAT3 activation in microglia [214]. On the other hand, IL-4 and IL-13 accelerate the loss of neurons under inflammatory conditions. Studies find that the levels of IL-4 and IL-13 are increased significantly with the treatment of neurotoxins [215,216,217]. In addition, IL-13Rα1 increases the susceptibility to LPS-induced oxidative damage of DA neurons [218], and deficiency of IL-13Rα1 delays the loss of DA neurons during chronic stress [219].

Clinical studies have found that two single nucleotide polymorphisms of IL-13 and IL13-RA1 (rs148077750 and rs145868092) increase the risk of PD [220], suggesting that IL-4 and IL-13 play an important role in the development of PD. However, the expression of IL-4 and IL-13 in PD patients and PD animal models is controversial. Some studies suggest that IL-4 expression is significantly increased in PD patients [157, 167, 221,222,223], and higher level of IL-4 is significantly correlated with the severity of tremors in PD patients [195]. IL-13 level is also significantly higher in plasma of PD patients compared with healthy controls [156, 193, 224]. However, other studies show quite different results [194, 225, 226]. Hühner et al. found that exogenous IL-4 protected mDA neurons from 1-methyl-4-phenylpyridinium (MPP+) induced loss in the presence of glial cells in vitro, and that primary microglia-derived IL-4 promoted neuroprotection by modulating the secretion of neuroprotective factors such as insulin growth factor-1(IGF-1). In vivo experiments demonstrated that the loss of IL-4 did not affect the susceptibility of mDA neurons to MPTP-induced damage, and nigrostriatal development was not impaired in IL-4 deficient mice [227, 228]. Interestingly, another study found that IL-4 was involved in LPS-induced SN neurodegeneration and microglial activation in vivo, which was related to upregulation of the pro-inflammatory cytokine IL-1β and disruption of the BBB and astrocytes [229]. The different effects of IL-4 in the two studies may be due to different drug administration and different cells.

IL-5

IL-5 is a type of cytokine secreted mainly by Th2 cells and ILC2s [230], and plays a key role in the development, differentiation and survival of eosinophils. IL-5 and its receptors have now become important targets for treating diseases such as asthma [231], chronic sinusitis [232], and hypereosinophilic syndrome [233]. The expression level of IL-5 in PD is different in different research groups. Di Lazzaro et al. [234]. and Hasan Kadhum al-Huchaimi et al. [235]. found that IL-5 was significantly reduced in PD patients compared with healthy controls, while Walker et al. found that the expression of IL-5 in protein level in SN of PD patients was higher than that in healthy controls or incidental Lewy body disease (ILBD) patients, and ROC curve analysis had significant predictive value [236]. It has been demonstrated that IL-5 promotes the proliferation and activation of microglia [237, 238], but how IL-5 affects the death of PD-related neurons is still unknown.

Th9-associated cytokines in PD

Although the function of Th9 cells in PD is unclear, its main cytokine IL-9 has potential pro-inflammatory effects. IL-9 is a multifunctional cytokine that is mainly produced by Th9 cells [239], but also secreted in small amounts by Th17 cells [240]. Studies have shown that IL-9 level is elevated in a variety of inflammation-related diseases, such as mild traumatic brain injury (mTBI) [241] and AD [242, 243], and has effects on the development of the diseases. In a mouse model of experimental autoimmune encephalomyelitis (EAE), Li et al. found that the KO of IL-9 reduced inflammatory cell invasion to the CNS, which downregulated IL-17, IFN-γ, TNF-α, and IL-12p70, and inhibited chemokine receptors CCR2, CCR5, and CCR6. Furthermore, IL-9 mediated Th17 cell differentiation was regulated by STAT1 and STAT3 [244]. Interestingly, another study showed that IL-9R KO increased granulocyte-macrophage colony-stimulating factor (GM-CSF) levels and the number of DCs, resulting in a more severe EAE phenotype [245]. Donninelli et al. also found that IL-9 played an anti-inflammatory role in multiple sclerosis (MS) by decreasing the activation of human macrophages and increasing the secretion of the anti-inflammatory cytokine TGF-β [246]. The contradictions in these results reflect the complexity of IL-9 functions, as IL-9 has been shown to promote the differentiation of Th17 cells and Tregs in different cellular environments [247]. Thus, IL-9 plays an anti-inflammatory role in PD, studies have found that the level of IL-9 in the CSF [158] and serum [248] of PD patients is significantly reduced compared with healthy controls, however, the mechanism of IL-9 in PD remains unclear.

Th17-associated cytokines in PD

Numerous studies have reported significant variations regarding level of Th17 cells among individuals with PD. Some studies indicate marked increases in the peripheral blood of PD patients while others suggest no change or even decreases. These discrepancies may be resulted from differences in assessing Th17 cell populations [249]. In animal models, MPTP-treated mice show a BBB disruption, resulting in a significant increase in Th17 cells and IL-17A in the SN [146, 250, 251]. Furthermore, adoptive transfer of nitrated α-syn (N-α-syn)-treated Th17 cells significantly enhanced MPTP-induced neurotoxicity [146]. Liu et al. have also demonstrated that Th17 cells exacerbate the loss of neurons in vitro [250]. All these provide direct evidence for the neurotoxic effects of Th17 cells. Additionally, Sommer et al. found that Th17 cells accelerated the death of midbrain neurons (MBNs) induced by PD patient-derived induced pluripotent stem cells (iPSCs). This may be due to the secretion of pro-inflammatory cytokines, such as IL-17, TNF-α, IL-1β, and IL-6 [252]. Studies in animal models have also shown that direct association between Th17 cells and neurons is mediated by the leukocyte function-associated antigen (LFA-1)/intercellular adhesion molecule (ICAM)-1 system, which leading to neuronal apoptosis [250]. Taken together, these findings suggest that Th17 cells and related inflammatory factors play a significant role in the pathology of PD (Fig. 4).

IL-17A/F

The IL-17 family is composed of six members (IL-17A-17F) that play essential roles in important processes such as host immune defense, autoimmune diseases, and cancer progression [253]. IL-17A is considered the hallmark cytokine of Th17 cells [254], and while its role in neurodegenerative diseases is still controversial, there is a study showing that IL-17A is involved in neuroinflammation and cognitive impairment in aged rats by activating microglia [255]. Both IL-17A and IL-17F bind to a heterodimer consisting of IL-17 receptor A (IL-17RA) and IL-17RC [256]. Similar to IL-17A, IL-17F also plays an important driving role in the inflammatory response [257].

Kebir et al. found that IL-17 and IL-22 disrupted the integrity of the BBB and promoted CD4+ lymphocyte migration [258]. This finding is supported by the observation of increased levels of IL-17 and IL-17-producing Th17 cells in both PD patients [157, 221] and PD animal models [196, 251, 259]. Additionally, Gate et al. demonstrated that α-syn stimulation promoted the expression of IL-17A in T cells of LBD patients, providing a possible explanation for the elevated level of IL-17 in PD patients [260]. Further clinical studies have also found that IL-17 is associated with non-motor symptoms in PD patients, including anxiety, depression, and cognitive impairment [261, 262]. However, some studies have reported significantly lower level of IL-17 in PD patients compared to healthy controls, reflecting the high heterogeneity of IL-17 in PD [194, 234].

In MPTP-treated mice, increased IL-17A activates microglia and aggravates the loss of DA neurons. This may be due to an increase in TNF-α, which is present in higher concentrations in IL-17A-treated microglia. However, this neurotoxicity is mitigated by TNF-α-neutralizing antibodies [251]. Sommer et al. have shown that Th17 cells from PD patients or IL-17 induces MBNs death through upregulation of IL-17R and activation of downstream nuclear factor κB (NF-κB). Blocking IL-17/17R or adding an FDA-approved anti-IL-17 antibody, secukinumab, reduces neuronal death [252]. Another study has also demonstrated that secukinuma reduces neuroinflammation in PD rats by blocking the interaction between IL-17A and IL-17RA [259]. Moreover, IL-17A and IL-17F also play pro-inflammatory roles by inducing the expression of other cytokines and chemokines, such as IL-1β, IL-6, TNF-α, granulocyte colony-stimulating factor (G-CSF), CXCL1, CXCL2, CXCL8, and CCL10 [72, 263]. In addition, IL-17A has been found to be helpful in maintaining intestinal homeostasis [264], and the intestinal microbiota has the ability to induce Th17 differentiation [265]. These findings will provide new insights for studying the relationship between PD patients and intestinal microbes.

IL-21

IL-21 is an inflammatory factor that is mainly produced by Th17 cells and Tfh cells. During chronic viral infections, IL-21 produced by CD4+ T cells directly or indirectly maintains the normal activity and function of CD8+ T cells by preventing CD8+ T cell exhaustion [266, 267] and reducing Tregs cell activity [268]. IL-21 also plays an important role in immune regulation in various neurodegenerative diseases, such as ALS [269] and AD. For instance, Agrawal et al. found that IL-21 contributed to neuroinflammation in AD mouse models by activating microglia and increasing the production of inflammatory cytokines such as TNF-α, IL-18, and IL-6 [270]. However, the function and mechanism of IL-21 in PD remain unclear.

IL-22

IL-22 is also a member of the IL-10 family, and its receptor, IL-22R, is a heterodimer composed of IL-22rα and IL-10Rβ subunits [271]. IL-22 is mainly produced by activated T cells, NK cells, ILCs, and neutrophils [272, 273], with Th17 cells being the main source [274]. IL-22 has been detected in various of tissues, including the gut, skin, lungs, liver, and eyes [275]. In addition, IL-22 is also expressed in human brain tissue, suggesting a potential role in the CNS diseases [276]. IL-22 has different anti-inflammatory or pro-inflammatory functions in different tissues, which depends on the environment and cytokines in which it is located [277].

IL-22 expression level is also significantly elevated in AD and PD patients or animal models [242, 278,279,280]. Mechanically, both IL-22 and IL-17 disrupt the BBB permeability, as demonstrated in EAE models [258]. In vitro studies have shown that IL-22 may improve the survival rate of human astrocytes through the anti-apoptotic pathway [276, 281]. Additionally, IL-22 activates microglia to produce more inflammatory factors, leading to neuronal death, which may be the main cause of neurodegeneration [277]. Furthermore, Lee et al. found that the interaction between IL-22 and IL-22Rα induced the production of pro-inflammatory factors TNF-α and IL-6 in BV2 and HT22 cells, and the c-jun N-terminal kinase (JNK) and STAT3 signaling pathways played an important role in this process [282]. However, IL-22 also plays an important role in inhibiting the inflammatory response. Gao et al. found that troxerutin, a clinical anticoagulant that acts as an IL-22 enhancer, increased IL-22 level in rats and activated the microglial IL-22R1/IRF3 system, promoting microglial M2 polarization. This leads to an increase in the anti-inflammatory factor IL-10 and a decrease in the pro-inflammatory factors IL-1β, TNF-α and IL-6 [283]. Therefore, a comprehensive understanding of the functions and mechanisms of IL-22 in neuroinflammation is very important for the treatment of neurodegenerative diseases.

Treg-associated cytokines in PD

Compared to healthy controls, the number of Tregs in the peripheral blood of PD patients is significantly reduced, and the proportion of Tregs is negatively correlated with the severity of motor symptoms, as measured by UPDRS-III scores [128, 284, 285]. This reduction of Tregs is also observed in animal models of PD. MPTP-treated PD mice exhibits fewer Tregs, and the adoptive transfer of Tregs reduces the brain’s inflammatory response and alleviated neuronal death [146, 286]. There is growing evidence suggesting that Tregs reduce neuroinflammation and promote neuronal survival by inhibiting glial cell activation [18, 146, 286,287,288,289,290]. Reynolds et al. demonstrated that the adoptive transfer of Tregs significantly reduced the inflammatory response of microglia, up-regulated the expression of BDNF and glial cell-derived neurotrophic factor (GDNF), and down-regulated the pro-inflammatory cytokines and oxidative stress, ultimately providing a protective effect on the nigrostriatum in MPTP-treated mice [146, 286, 287]. Furthermore, Tregs have been shown to protect neurons through a cell-contact dependent manner. Huang et al. revealed the protective function of Tregs on MN9D cells, a mDA neuronal cell line, and ventral mesencephalic neurons in vitro through the interactions of CD45-galectin-1 and CD47-SIRPA, respectively [291, 292]. These experimental data provide strong support for the role of Tregs in neuroprotection. (Fig. 4)

IL-10

IL-10, an anti-inflammatory and immunosuppressive cytokine produced by both innate and adaptive immune cells, plays an important role in the development of numerous chronic human diseases associated with inflammation [293]. Recent studies have demonstrated that IL-10 also plays a role in neuroinflammation-related neurodegeneration such as MS, traumatic brain injury, amyotrophic lateral sclerosis, AD, and PD, and is now a potential target for the treatment of neurodegenerative diseases [294].

As an anti-inflammatory factor, the expression level of IL-10 in the PD peripheral blood is significantly lower than that in healthy controls [194, 234], and it is negatively correlated with the severity of patients [295] and non-motor symptoms such as PD-related pain [296] and gastrointestinal symptoms [155]. IL-10 level is also significantly reduced in animal models of PD [161, 297, 298]. Mechanistically, IL-10 inhibits glial cell activation and neuronal loss by down-regulating pro-inflammatory mediators, TNF-α, IL-1β, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) and up-regulating anti-inflammatory factors, such as BDNF, insulin-like growth factor-1, TGF-β and GDNF [299,300,301,302]. Zhu et al. found that IL-10 reduced LPS-induced neuronal loss, while silencing of IL-10 receptor and blocking of Janus kinase (JAK)-STAT3 pathway abolished IL-10 mediated neuroprotective effect [303]. IL-10 also inhibited the synthesis, activation and cleavage of NLRP3, pro-caspase-1 and pro-IL-1β by inhibiting the production of LPS-induced intracellular ROS in vitro. Through this mechanism, IL-10 reduces the occurrence of neuroinflammation [304]. In addition, IL-10 can be regulated by other regulatory factors. For example, the transcription factor myocyte enhancer factor 2D (MEF2D) binds to the promoter of IL-10 and promotes its transcription, thereby inhibiting microglia-mediated cellular inflammation [305].

However, some other studies have found that the expression level of IL-10 in PD patients is significantly increased [154, 167, 222], which reflects the dual function of IL-10 in inflammatory response. Cockey et al. demonstrated that IL-10 and its anti-inflammatory variant I87A variant (v)-IL-10 resulted in shortened lifespan, accelerated α-syn pathology, microglial proliferation and increased apoptosis in A53T PD mice [306]. Therefore, a comprehensive understanding of the mechanisms of IL-10 is essential for the diagnosis and treatment of PD.

IL-35

IL-35 is a newly discovered member of the IL-12 family, consisting of IL-27β chain Ebi3 and interleukin-α chain p35 [307]. IL-35 is an anti-inflammatory cytokine secreted mainly by Tregs and B cells [307, 308]. Recent studies have revealed abnormal expression and function of IL-35 in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis (RA), EAE and MS [309, 310]. Although the role of IL-35 in PD is not well understood, studies have shown that levels of Tregs and their related cytokines IL-35 and TGF-β are correlated with cognitive impairment in AD patients [311]. In addition, Lin et al. have demonstrated that IL-35 has an anti-pyroptosis effect in primary microglia stimulated by LPS and adenosine triphosphate (ATP) [312]. Therefore, it is important to further explore the mechanisms of IL-35 in neurodegenerative diseases, including PD.

TGF-β

Currently, three highly conserved subtypes of TGF-β, named TGF-β1, TGF-β2, and TGF-β3, have been identified in mammals with similar sequence homology [313]. Increasing studies have shown that TGF-β is a negative regulator of inflammation and plays an important role in neuroprotection. TGF-β is essential for the growth and survival of neurons. The double KO of TGF-β2 and TGF-β3 in the embryonic stage results in a significant reduction of DA neurons in the midbrain of mice [314]. Reduced TGF-β signaling in mature neurons also leads to motor deficits and degeneration of the nigrostriatum in mice. By increasing TGF-β signaling in the SN, MPTP-induced DA neuron loss and motor deficits can be significantly reduced [315]. In addition, TGF-β also regulates the differentiation and development of neuronal axons both in vivo and in vitro [316]. Roussa et al. [317]. found that TGF-β, together with Shh and FGF-8 (two factors necessary for the development of mDA neurons), promoted the survival of mDA neurons, while loss of TGF-β1 led to neuronal apoptosis, and neutralization of TGF-βs reduced neuronal death [318, 319]. The protective effect of TGF-β1 on DA neurons results from its ability to block IFNγ-induced microglial activation by inhibiting STAT1 phosphorylation and IFNγRα expression, thereby improving neuronal survival [320]. Studies have also found that TGF-β plays a key role in regulating astrocytes [321]. Removal of TGF-β3 from the medium significantly increased the expression of astrocyte associated markers (GFAP and S100B), while decreasing the expression of DA phenotype-associated markers such as FOXA2 and TH [322].

The anti-inflammatory and neuroprotective properties of TGF-β indicate that it may play an important role in neurodegenerative diseases such as PD. Indeed, higher level of TGF-β has been found in the serum [323] and CSF [324] of PD patients, which may be related to the accumulation of α-syn. Diniz et al. demonstrated that α-syn oligomers (αSO), the most toxic components in PD pathology [325], induced the secretion of TGF-β1 by astrocytes, which promoted the formation of glutamatergic synapses and protected neurons from damage [326]. In in vitro experiment, TGF-β1 treatment significantly inhibits the expression of inflammatory factors in microglia induced by MPP+, and reduced the loss of DA neurons by activating TGF-β receptor (TβR)-I and its downstream p38 mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways in microglia [327]. In a mouse model of PD, intraventricular administration of TGF-β1 improved MPP+-induced microglial activation and inflammatory cytokine production, and alleviated MPP+-induced dyskinesia and behavioral changes [328]. However, it is worth noting that while TGF-β1 has a neuroprotective effect, long-term exposure to it can also have negative effects on neurons. Martinez-Canabal et al. found that transgenic mice overexpressing TGF-β1 in astrocytes had changes in brain structure, especially a significant increase in the hippocampus volume. This led to an increase in the number of granulosa cells within the dentate gyrus (DG) of the hippocampus and ultimately resulted in spatial learning deficits [329]. In addition to TGF-βs, other members of the TGF-β superfamily, such as activins [330], growth and differentiation factors (GDFs) [331], and bone morphogenetic proteins (BMPs) [332], also play vital roles in the regulation of neuroinflammation and the development of PD.

Fig. 4
figure 4

The regulation mechanisms of Th17 and Tregs cells in PD. In animal models of PD, disruption of the BBB results in a significant increase of Th17 cells and cytokines in the SN. Studies have shown that Th17 cells come into direct contact with neurons via the LFA-1/ICAM-1 system in vitro, which leads to neuronal death. Tregs are a subset of anti-inflammatory cells that reduce neuroinflammation and promote neuronal survival by inhibiting the activation of glial cells. Tregs protect neurons through CD47-SIRPA interaction in vitro

Full size image

Tfh-associated cytokines in PD

Zhao et al. discovered a significant increase in the proportion of peripheral Tfh cells in PD patients compared to healthy controls [333]. In contrast, Li et al. observed a decrease in the number of Tfh cells in PD patients, which was associated with a decrease in Ki-67+ B cells [334]. At present, there are no studies on the mechanism of Tfh cells in PD. The functions of Tfh cytokines IL-4, IL-10 and IFN-γ in PD are discussed in detail in Sect. 3.2.1, 3.1.3 and 3.5.1, respectively.

Immunotherapy for PD

As the global population ages, the risk of developing neurodegenerative diseases such as PD is on the rise. Currently, there are no pharmacological treatments available to completely stop or reverse the progression of PD. Therefore, it is imperative to identify an effective treatment. While current PD treatments primarily involve levodopa or dopamine receptor agonists, these medications provide symptomatic benefits only and do not halt disease progression, may not adequately treat all the symptoms of PD especially non-motor symptoms, and can cause adverse side effects [335]. Given the important role of neuroinflammation in the pathological development of PD, immunotherapy has become a potential approach to alleviate PD disease. At present, immunotherapies targeting CD4+ T cells have become an important means of treating PD. This section provides a summary of clinical trials targeting CD4+ T cells in PD.

Immunotherapy targeting CD4+ T cell-related cytokines

Given the important role of inflammatory response in PD, small molecule drugs targeting inflammatory cytokines, especially antagonists of pro-inflammatory factors, have become a potential treatment for PD (Table 1).

Table 1 Drugs targeting cytokines for the treatment of PD
Full size table

TNF-α inhibitors

Currently, TNF-α inhibitors worldwide mainly include infliximab, adalimumab, certolizumab, golimumab, and etanercept, which provide effective treatment options for a variety of inflammatory diseases. Infliximab [336], adalimumab [337], certolizumab [338], and golimumab [339] are anti-TNF-α monoclonal antibodies, and play important roles in anti-inflammation. In a clinical study, Peter et al. observed that IBD patients who received anti-TNF therapy (infliximab, certolizumab, adalimumab and golimumab) had a significantly lower incidence of PD compared to IBD patients who did not receive anti-TNF therapy. This study suggests that these anti-TNF drugs have the potential to treat PD [340]. Etanercept is a fully humanized soluble recombinant TNF receptor fusion protein [341], which is now used to treat a variety of diseases such as RA [342], psoriasis [343], psoriatic arthritis [344] and ankylosing spondylitis [345]. In in vivo assay, etanercept mitigated the LPS-induced inflammatory response and the microgliosis and astrocytosis in rats, attenuating systemic and local inflammation [346].

IL-1 receptor antagonist

Anakinra (Kineret) is a recombinant human IL-1 receptor antagonist that inhibits IL-1 by binding to IL-1 type 1 receptors. Anakinra is the first biological agent approved to block the pro-inflammatory effects of IL-1 in patients with RA [347]. In addition, anakinra has also achieved good results in clinical trials for diseases such as type 2 diabetes [348], coronavirus disease (COVID-19) [349], intracerebral haemorrhage [350], gout [351], and elevated myocardial infarction [352]. In 6-OHDA-induced rat models of PD, anakinra significantly reduces levels of TNF-α and IFN-γ, and mitigates the loss of DA neurons [353].

IL-17A/IL-17RA inhibitors

There are currently five IL-17A/IL-17RA inhibitors in various stages of clinical development: secukinumab, ixekizumab, brodalumab, netakimab, and bimekizumab [354]. However, only secukinumab has been demonstrated to have neuroprotective properties. Secukinumab selectively targets IL-17A and inhibits its interaction with the IL-17 receptor, thereby inhibiting the release of pro-inflammatory cytokines and chemokines [355]. In rotenone-induced PD rat models, secukinumab exerts neuroprotective effects by inhibiting IL-17A/IL-17RA interaction and activation of TLR-4 and its downstream signaling pathway, as well as activating the TrKB/Akt/CREB/BDNF axis [259]. Additionally, secukinumab rescued neuronal death in vitro [252].

ROR-γt inhibitors

As an important transcription factor, ROR-γt promotes the differentiation of Th17 cell and the expression of IL-17, which plays a pivotal role in the neuroinflammation of PD [78]. Thus, drugs targeting ROR-γt interferes with Th17 differentiation and inhibits the production of multiple inflammatory cytokines, thereby reducing the inflammatory response. Li et al. discovered that the ROR-γt inhibitor GSK805 hindered the increase of Th17 cells, the decrease of Tregs, and the apoptosis of DA in MPTP-treated mice [284].

Tregs inducers

Tregs are indispensable for maintaining normal immune tolerance due to their powerful anti-inflammatory function. A recent study demonstrated that Tregs autologous co-transplantation effectively reduced the needle-trauma-induced death of mDA neurons during cell therapy [356]. Drug-induced enhancement of Tregs function also has been shown to provide neuroprotection for DA neurons and improve clinical scores and prognostic outcomes in PD patients. Currently, Tregs inducers in animal studies or clinical trials mainly include GM-CSF and vasoactive intestinal peptide (VIP). GM-CSF, an inflammatory cytokine, exerts its anti-inflammatory activity primarily by regulating the differentiation of tolerant DCs, leading to an increase in the number and function of Tregs [357]. At present, GM-CSF is undergoing evaluation in clinical studies. In a randomized, double-blind phase 1 clinical PD trial, after 2 months of daily administration of sargramostim (a recombinant human GM-CSF), cortical motor activities, Tregs numbers and function improved in PD patients [358]. VIP is another promising immunomodulatory agent that plays a neuroprotective role by increasing the number and function of Tregs while reducing microglial inflammatory response [146]. In particular, VIP receptor 2 (VIPR2) agonist LBT-3627 increases Tregs activity, inhibits astrocyte proliferation, and reduces neuroinflammation, providing a basis for follow-up immunotherapy in PD patients [359, 360]. Additionally, histone deacetylase (HDAC) inhibitors [361] and RA [362] also play important roles in Tregs-mediated immunotherapy.

Other treatments for PD

In addition, non-steroidal anti-inflammatory drugs (NSAIDs) [363], traditional Chinese medicine (TCM) [364], probiotics [365], vitamin D [366], electrical stimulation [367], stem cell therapy [368], all have proposed anti-inflammatory effects and have been used in the treatment of PD, with varying success.

NSAIDs

NSAIDs are a common analgesic and anti-inflammatory drug that can be absorbed from the stomach and intestinal mucosa and cross the BBB, thereby affecting the CNS [369]. NSAIDs affect PD neuropathology in different ways, producing beneficial, neutral and even harmful effects on neurons. On the one hand, NSAIDs provide neuroprotective effects on the progression of PD neuropathology by inhibiting the expression levels of COX-2 [370] and LRRK2 [371] and their associated inflammatory responses, enhancing endocannabinoid signaling [372] and restoring the activity of serotonergic neurons [373]. On the other hand, long-term use of NSAIDs may adversely affect PD neuropathology by inhibiting the neuroprotective effects of COX-2 and prostacyclin (PGI2) and enhancing the pro-inflammatory Leukotrienes (LTs) pathway. Therefore, a comprehensive understanding of the pharmacological effects of NSAIDs is essential for the treatment of PD [363].

Traditional Chinese medicine

TCM is a complete system of ancient Chinese medical theory and practice with a history of thousands of years. In recent years, TCM has attracted more and more attention in the treatment of PD because of its unique theoretical basis and clinical effect [364]. For example, gastrodin, the main bioactive component of Gastrodiae Rhizoma, has the effect of alleviating neuroinflammation associated with PD both in vivo and in vitro. Li et al. found that gastrodin protected DA neurons by inhibiting the expression of IL-1β and TNF-α in the SN of rotenone-induced PD rats [374]. In addition, Huang et al. found that Berberine alleviated NLRP3-associated neuroinflammation by enhancing autophagy activity in MPTP-induced mice and MPP+ treated BV2 cells in vivo and in vitro [375].

Probiotics

Gastrointestinal dysfunction is one of the most common non-motor symptoms in PD patients, with a prevalence of more than 80% [376]. Studies found that probiotics changed the composition of the PD-associated microbiota, thereby improved the gastrointestinal function of patients [377, 378]. However, the mechanism by which probiotics treat PD remains unclear. An in vitro study showed that probiotics reduced the expression of pro-inflammatory cytokines and oxidative stress in peripheral blood mononuclear cells (PBMC) of patients with PD [379].

Vitamin D

Vitamin D is a fat-soluble steroid vitamin that exists in nature in two main forms, vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) [380]. In recent years, the role of vitamin D in neurodegenerative diseases, particularly in PD, has received attention. In MPTP-induced PD mouse models, vitamin D treatment reduces DA neurodegeneration by upregulating the expression of anti-inflammatory cytokines (IL-10, IL-4, and TGF-β) and the M2 anti-inflammatory phenotype of microglia [381]. In addition, vitamin D can also reduce the cytotoxicity caused by α-syn aggregation by inhibiting ROS production [382]. In clinical studies, increasing vitamin D consumption has been shown to alleviate symptoms in PD patients. A randomized, double-blind trial found that the balance of younger PD patients (ages 52–66) was improved after taking high-dose (10,000 IU/day) of vitamin D for 16 weeks [383].

Electrical stimulation

Deep brain stimulation (DBS) is being widely used as a clinical intervention in the treatment of neuropsychiatric disorders, including PD. The primary target region for DBS electrodes is the subthalamic nucleus (STN), which plays an important role in motor function [384]. In 6-OHDA-induced PD rat models, STN-DBS inhibited the secretion of pro-inflammatory factors and promoted the expression of anti-inflammatory factors, and inhibited the activation of microglia and astrocyte, which played an anti-inflammatory role in PD [385, 386].

Stem cell therapy

Stem cells are a class of cells that have the potential to self-renew and differentiate into different cell types. According to their source, differentiation potential and characteristics, stem cells can be divided into many types, such as embryonic stem cells (ESCs), iPSCs, mesenchymal stem cells and neural stem cells [387]. Stem cell therapy is a promising treatment for neurodegenerative diseases, including PD, because of its angiogenesis, immunomodulatory, neuroprotective and anti-inflammatory functions [388, 389]. For example, a study found that human ESCs (hESCs)-derived MBNs projected long distance in the brain and restored their motor function of rat PD models [390]. Another study from non-human primates found that human iPSCs-derived DA neurons improved the spontaneous motor capacity of MPTP-induced monkey PD models (Macaca fascicularis) and showed ample neurite formation [391]. However, stem cell-based therapies have shown different results in PD, so further study is still needed in future.

Conclusions

In order to protect the host from foreign invasions, the immune system has evolved a series of intricate response mechanisms. CD4+ T cells are an integral part of adaptive immunity, in which different CD4+ T cell subsets play specific roles. PD is the second most common neurodegenerative disease, and neuroinflammation is an important risk factor for it. In this review, we describe the differentiation regulation of different CD4+ T cell subsets and their functions and mechanisms in PD, as well as summarize immunotherapies targeting CD4+ T cells, with a view to providing new strategies for the diagnosis and treatment of PD.

The hallmark of PD pathology is the loss of DA neurons, so the current treatment of PD is mainly through the supplementation of reduced dopamine, such as levodopa and dopamine receptor agonists. In general, levodopa and dopamine receptor agonist are symptomatic treatments only, do not modify disease course and sufficiently address all the symptoms of PD, especially non-motor symptoms. As a potential alternative, immunotherapy targeting CD4+ T cells may become a potential treatment for PD. Although there are many immunotherapies targeting CD4+ T cells and their cytokines, progress in clinical research has been slow. Therefore, accelerating the research on CD4+ T cells in PD will provide new theoretical guidance for us to develop more effective targeted drugs.