The interplay between the innate and adaptive arms of the immune system is essential to the relationship between neuroinflammation, neuroprotection, and neurodegeneration. While neuroinflammation and neurodegeneration are associated with the pathobiology of neurodegenerative diseases, they are also responsible for the overall neuroprotective homeostasis of the host CNS in infectious or neoplastic disease surveillance. Similarities between multiple neurological disorders have provided common mechanisms of immune interactions that lead to protective or destructive effects within the CNS and peripheral nervous system (PNS). Although neuroinflammation and T cell interactions play a prominent role in disease progression, it should be noted that the immune response can vary from a very prominent primary T cell response, as in multiple sclerosis (MS), to seemingly less intense, though present, T cell response as in the cases of amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, it should also be noted that detrimental secondary inflammatory responses are observed in these neurodegenerative diseases, particularly in AD, PD and ALS, thus this commonality warrants further elaboration. Recent findings in human neurodegenerative disorders and in corresponding animal models have shown the involvement and putative mechanisms of T cells and subsequent secondary responses in disease initiation and progression.
Multiple sclerosis
MS is a chronic, progressive demyelinating inflammatory disorder that is principally driven by T cells specific for self-antigens expressed in the myelin sheath[
25,
26]. This notion is supported largely by data showing the presence of activated myelin-reactive T cells as well as CD4+ T cell infiltrates in MS patients affect the disease course[
27‐
29]. As such, therapeutic modalities and clinical trial strategies have primarily targeted components of the immune system. While no modality has proven to be curative, and clinical trial outcomes varied extensively with little to no efficacy, some with beneficial effect, and others with devastating side effects, results have furthered our understanding on the pathogenesis of MS[
30].
Evidence supports activated CD4+ myelin-reactive T cells as a driving force behind MS[
29]. However, a compounding complexity of the disease arises from the finding that both healthy controls and MS patients have similar numbers of circulating T cells reactive to components of myelin[
29]. Thus, the mere presence of self-reactive T cells is not sufficient evidence to explain the development of MS. Prior to the discovery of Th17 cells, MS was considered a purely Th1-mediated disease. However, recent studies lead to the view that MS is neither a purely Th1- nor Th17-mediated disease. As with EAE, both Teff subtypes are thought to participate in the pathology of MS, but with relative dominance of each Teff type playing a critical role in the progression of MS, affecting the temporal course and clinical variants[
27]. For instance, T cells stained for expression of IL-17 are reported to be higher in early active plaques compared with chronic active or inactive plaques[
31]. Similar
ex vivo data showed that peripheral blood mononuclear cells (PBMCs) derived from MS patients taken within 2 years of diagnosis produced higher levels of IL-17
in vitro compared with those taken from patients with long-standing disease[
32].
The frequencies of Tregs in both the blood and cerebral spinal fluid (CSF) of MS patients have been extensively investigated[
33‐
36]. Interestingly, when brain tissue was examined from 16 untreated MS patients, no Tregs were found in 30% of the biopsies, and the number of FoxP3+ cells was generally low in the brain tissue[
37] suggesting Tregs may not be capable of infiltrating the CNS in MS patients, and therefore, immune responses are un-regulated. While further studies showed no significant differences in the number of Tregs from the peripheral blood or CSF of MS patients compared to healthy controls, the functional capabilities of Tregs were impaired in patients suffering from MS[
38].
The functional impairment of Tregs from MS patients could not be attributed to a higher activation status of Teffs, but rather seemed intrinsic to the Tregs themselves[
38]. Indeed, experiments examining Treg functionality led by separate investigators found MS patients had lower mRNA and protein expression levels of the Treg transcription factor, FOXP3, when compared to healthy controls[
38‐
40]. Venken
et al. made similar findings in patients suffering from relapsing-remitting MS. However, FOXP3 expression and Treg functionality was normal during secondary progressive MS[
40]. Whether Treg dysfunction in MS represents a general defect in the regulatory network of the immune system, and as such is a causative factor, remains to be elucidated[
38].
Experimental autoimmune encephalomyelitis (EAE) has been the primary model of CNS autoimmune disease for over half a century[
41]. The use of EAE has expanded the understanding of immune regulation of autoimmune disease. Furthermore, the EAE model affords evidence reaching beyond MS, providing mechanisms by which Teffs gain entry into the brain[
6]. In adoptive transfer studies of EAE, researchers have shown that myelin-reactive T cells polarized to either a Th1 or Th17 phenotype are capable of initiating disease in recipient mice, but the histopathological outcome from the two T cell populations were distinct. In animals that received Th1 polarized cells, macrophages were more prominent, whereas Th17 recipient mice showed a more severe neutrophil infiltration[
42]. This suggested that while both Th1 and Th17 cells play a role in de-myelination and disease progression, their mechanisms of destruction may be different. In addition to demonstrating different subsets of Teffs that elicit different pathological signs in EAE, studies also showed a temporal involvement of Th1 and Th17 in disease progression. Results demonstrated an early involvement of Th17 cells, with Th1 cells becoming predominant prior to disease resolution. Dardalhon and colleagues proposed this shift in polarization might be related to the natural course and recovery from an attack of EAE[
43].
To address the role of CD25+ T cells in autoimmunity, Sakaguchi and colleagues demonstrated that nude mice reconstituted with CD4+ T cells depleted of the CD25+ subpopulation of cells developed spontaneous autoimmune disease[
44]. Replenishment of the CD25+ cell population prevented this development of autoimmune diseases. This suggested the presence of a naturally arising subset of T cells that acted to limit the response to self-antigens[
41]. Several more recent studies showed that Treg depletion prior to EAE induction increased the severity of the disease[
41,
45‐
47] indicating that Tregs suppress expansion of autoreactive effector cells.
Amyotrophic lateral sclerosis
ALS is a progressive neurodegenerative disease of unknown origin that primarily affects upper and lower motor neurons located at the ventral horn of the spinal cord, brain stem, and motor cortex[
48]. These regions control voluntary muscle movement, leading to paralysis, respiratory failure, and ultimately, death with disease progression[
49]. Although the etiology remains enigmatic, many factors and genetic mutations contribute to the pathobiology of the disease in some cases. In familial ALS (fALS), mutation of genes such as those that encode Cu/Zn superoxide dismutase (SOD-1) on chromosome 21 or alsin that encodes a ras GTPase have been linked to ALS patient populations[
50,
51]. Currently over 20 different genes have been associated with fALS; however, the majority of ALS cases are sporadic and not linked to familial or genetic factors. As a contributing factor, neuroinflammation is thought to play a prominent role, and is supported by evidence of reactive microglia and astrocytes as well as infiltrating T cells found at affected sites and implicated in disease pathogenesis[
52]. The interplay between nervous and immune systems results in an inflammatory response, which can be detrimental or protective depending on the disease state. Activated Teffs have the ability to penetrate the BBB and carry out their immune functions in the CNS[
53], and inflammation has been thought to play a crucial role in the death of motor neurons[
54], suggesting that perhaps an aberrant adaptive immune response is occurring.
Substantial numbers of infiltrating T cells and macrophages are found in the spinal cords of patients[
55,
56]. The majority of these migrating T cells are described as CD8+ cytotoxic T cells with CD4+ T cells usually comprising a minority of lymphocytes. A considerable number of T cells are in close proximity to vessels near sites of neurodestruction[
57], while little or no T cell infiltration is found in spinal cords of controls. An immunohistochemical study by Engelhardt
et al. found both perivascular and intraparenchymal lymphocytic infiltrates in the post-mortem spinal cords of 18 ALS patients[
6]. Virtually all lymphocytes were T cells with little B cell infiltration, suggesting a T cell specific mechanism of destruction. Mostly, activated CD4+ T cells were found near degenerating spinal tracts in ALS patients[
58]. Apart from direct migration into affected areas such as the spinal cord, more immune aberrations have also been documented in the periphery. For instance, the frequencies of CD4+ T cells are increased in the peripheral blood of sporadic ALS patients as well as increased expression of antigen presenting molecules like HLA class II on APCs, suggesting systemic immune activation in those patients[
59]. While these changes are found primarily in the periphery, those occurring in the CNS may be quite different. Indeed, Teff types found infiltrating the CNS were characteristic of Th17 and Th1, suggesting the involvement of IL-17, IFN-γ, TNF-α and IL-6 proinflammatory cytokine production and roles for both Th17 and Th1 in ALS progression[
60]. These proinflammatory cytokine-producing CD4+ cell types were increased in ALS patients compared to controls, as well as IL-17 producing cells and total levels of IFN-y, thus suggesting that the increased proinflammatory milieu plays a substantial role in exacerbation of motor neuron death. On the other hand, T cells expressing neurotrophic factors such as BDNF were also increased, which suggested that although Th1 and Th17 Teffs dominate the response in progressive ALS, neurotrophic responses also may be involved in determining the tempo of disease progression.
In addition to the increase in Teff populations and pro-inflammatory cytokine levels associated with ALS progression, Treg (CD4+CD25+) levels are decreased in peripheral blood and are correlated with increased disease progression[
61]. Since Tregs possess the capacity to harness overactive immune responses, reduction of Treg levels may indicate a deficit in the ability of the patient to suppress an overactive and aberrant immune response. To support that notion, one study found that the numbers of Tregs and FOXP3 protein expression were reduced in progressive ALS patients, and this reduction correlated with disease progression[
62]. Thus, these data suggest the importance of FOXP3 to bestow a functional ability of Tregs to suppress Teff subsets, and lack of FOXP3 expression could result in aberrant immune responses that may accelerate disease progression.
Studies using animal models of ALS show that Teffs and Tregs play differing roles in the pathobiology of ALS. In a study carried out by Beers
et al., T lymphocytes were observed infiltrating into lumbar regions of the spinal cord, as well as the cervical regions during disease progression. Initially, the T cell subset was considered Th2 due to the predominant expression of GATA3 transcription factor[
63]. However, as the disease progressed, IFN-γ and T-bet were upregulated, which are indicative of a Th1 phenotype, suggesting that T cell subsets modulate with disease progression or
vice versa. This shift may also correlate with a shift in microglial state. At an early disease stage, microglia show a protective M2 phenotype, but with disease progression, microglia shift towards a pro-inflammatory or neurotoxic M1 phenotype[
64]. Also, in mutant SOD1 G93A mice, numbers of CD4+ and CD8+ T cells increase, as well as activation of microglia, and inclusion of the mutant SOD1 gene onto mice without functional T cells or CD4+ T cells accelerated disease progression suggesting T cells or CD4+ T cells are beneficial in SOD1 mice[
65,
66]. However, increases in CD8+ T cells are typically seen only in late stage ALS[
66], whereas CD4+ increases are seen earlier, suggesting an interplay between immune activation and neurodegeneration in this disease. In one study, knocking out CD4+ cells decreased microglial reactivity suggesting a direct interaction between CD4+ T cells and glial cell activation[
66]. However, another study showed conflicting results, wherein mutant SOD1 mice lacking functional CD4+ T cells presented accelerated motor neuron degradation, suggesting the importance of CD4+ T cells for neuroprotective effects in ALS[
67]. Alternatively, this data may support a role for the neuroprotective capabilities of CD4+CD25+ Tregs and potentially other CD4+ subtypes. Therapeutic vaccination for motor neuron disease has also been addressed using Copolymer 1 (Cop-1, glatiramer acetate, GA), which has been shown to mediate a protective T cell response. Treatment with Cop-1 protected motor neurons against degeneration and doubled the number of surviving neurons when compared to untreated controls[
68]. On the contrary, a conflicting study showed that therapeutic vaccination with a high molecular weight derivate of GA does not alter survival and does not confer neuroprotection in mutant SOD mouse models[
69].
Besides the detection of a Th1 phenotype and increased microglial reactivity in ALS mouse models, the benefits of Treg-mediated protection of motor neurons have been reported. In mSOD1 mice, Treg numbers that produce IL-4, IL-10, and TGF-β are increased in early disease onset suggesting that immunosuppressive capability may delay disease progression[
70,
71]. Co-cultured with Teffs, Tregs from animals in early stages were effective at inhibiting proliferation using cytokine mediators. However, later in disease, Treg numbers were decreased, and the ability to inhibit Teff proliferation was diminished suggesting a functional deficit in those Tregs[
70,
71]. Indeed, disease progression accelerated with diminished Treg function. Together, these data support the importance for Treg-mediated suppression of detrimental immune responses associated with the disease and in slowing the tempo of disease progression. Another study from our own laboratory, using T cell adoptive transfer into the mutant SOD1 G93A model, found that transfer of either activated Teffs or Tregs from wild-type mice delayed disease onset, loss of motor function, and extended survival[
14]. Moreover, only transfer of Tregs delayed onset of clinical signs, whereas transfer of Teffs increased the latency between disease onset and entry into late stage disease. These results indicate that CD4+ T cells, regardless of phenotype, may induce some protection in the mouse model of ALS depending on the stage of the disease. For instance, during early stages of disease, CD4+ Tregs may enhance M2, instead of M1 microglial phenotypes. However, at end stage of disease when cytotoxic CD8+ T cell numbers are found to increase and Treg-mediated neuroprotective capabilities are diminished[
67], transfer of anti-CD3 activated Teffs may function at several levels such as increased production of anti-inflammatory mediators or increased FAS-mediated lytic capabilities that can both act on either activated microglia or neurotoxic Teffs.
Another neuroprotective strategy is the selective knock down of mutant SOD1 in neuronal and non-neuronal cell types of the CNS. In order to determine whether diminution of mutant SOD levels affected disease progression, mice carrying deletable mutant genes were utilized. Deletion of mutant SOD1 from motor neurons delayed onset of disease and progression through early stage[
72,
73]. Because glial activation is an accepted hallmark of mutated SOD1 in ALS, researchers began to address levels of mutant protein expression in glial cells and their effect on disease. Selective deletion of mutant SOD1 in microglia resulted in extended survival due to the significant delay of post-onset disease progression beyond that observed in selective deletion from motor neurons[
72,
73]. Deletion of mutated SOD1 in astrocytes while delaying activation of microglia, did not affect disease onset or early stage disease, but delayed late stage disease progression[
74]. Together, these data suggest that limiting mutant levels in both neurons and non-neuronal cell types slow disease onset and progression and increase survival. Thus therapeutic targeting of mutant SOD1 expression by microglia or astrocytes may prove beneficial in the treatment of ALS.
Alzheimer’s disease
AD is the most common form of dementia-producing neurodegenerative disorders. Pathologically, cortical and subcortical neurons and synapses are preferentially and progressively lost with histological hallmarks of neurofibrillary tangles and extracellular amyloid-beta (Aβ) plaques[
75]. The formation of these histological hallmarks is thought to contribute to neuronal death in areas such as the hippocampus and cortex resulting in several behavioral and cognitive impairments. Disease risk factors include both genetics and environment. Moreover, increased neuroinflammation due to microglial responses from neuronal loss and aberrantly cleaved and folded protein components is implicated as well as BBB dysfunction and lymphocyte infiltration[
76].
Indeed, multiple studies suggest that neuroinflammation in the CNS of AD patients is associated with increased T cell infiltration[
76‐
79]. Immune profiling of peripheral blood from AD patients shows significant aberrations in immune populations which may be associated with disease progression[
80]. T cells and B cells are diminished, with substantial changes in CD4+ and CD8+ T cell populations. Larbi
et al. have found a significant decrease in the frequencies of naïve CD4+ T cells, with concomitant increases in effector memory T cells in AD patients[
81]. Frequencies of CD4+CD25+ Tregs were also reduced. Another study confirmed the decrease in total CD3+ T cells as well as decreased numbers of B cells[
82]. Interestingly, CD4+ T cell subsets were increased while CD8+ T cell numbers were decreased. However, other studies have detected no significant changes in CD8+ T cell numbers or cytokine levels in AD patients[
83]. Additionally, the levels of different T cell subsets detected are greatly variable, but each study documents some systemic immune aberrations in a CD4+ T cell population. One study noted, in combination with T cell subset changes, CD8+CD28- suppressor cells were decreased among PBMCs from AD patients, as well as IL-10 production[
84]. These data suggest that the immunosuppressive capabilities in AD patients are diminished and could represent a deficit in the ability to control Teff responses. Similarly, increased activities of Th17 and Th9 subsets have been found in AD patients[
85]. Indeed, levels of the proinflammatory cytokines IL-21, IL-6, and IL-23, and the Th17-associated transcription factor RORγ, were increased among lymphocytes in AD patients. Moreover, IL-9 was produced in significantly higher levels by cells from AD patients. Together, these data are indicative of increased levels of functional Th17 and Th9 phenotypes, which may lead to profound skewing of an inflammatory immune response in those patients.
Animal models of AD have shown increased numbers of infiltrating neutrophils, macrophages, and T cells into the CNS from the periphery, possibly through BBB dysfunction[
86,
87]. Specifically for T cells, Th1 cells secreting IFN-γ and Th17 cells producing IL-17 were present in the CNS in amyloid precursor protein/presenilin 1(APP/PS1) mutant mice[
88]. Interestingly, peripheral immune activation using respiratory infection also increased T cell infiltration into the brains of AD mice[
89]. In those animals compared to controls, frequencies of CD3+ T cells were significantly increased as well as those of CD4+ and CD8+ T cells, proinflammatory Th1 and Th17 Teffs, microglia, and expression of pro-inflammatory genes encoding TNF-α, IL-1β, and IL-6. These increased levels of proinflammatory immune cells and mediators corresponding to increased levels of soluble and insoluble Aβ as well as increased numbers of plaques. Another study, in a rat model of AD, showed increased IL-17 and IL-22 cytokine production in the hippocampus that further supports the role of Th17-mediated promotion of microglial activation leading to increased neuroinflammation and neurodegeneration in AD and AD models[
87]. Together, these data suggest that specific Teffs may provide neurotoxic conditions such that they contribute to the inflammatory cascade associated with AD and exacerbation of disease progression. Additionally, blood vessels near Aβ deposits express high levels of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), contributing to the extravasation of activated, antigen-specific (Aβ) T cells from the periphery[
90]. Possibly, drainage of inflammatory mediators with aggregated and modified Aβ from the CNS provide sources of activating agents and modified self-antigen for APCs such as dendritic cells to induce Aβ-specific T cells. In turn, activated T cells could enter the CNS to inflamed sites via gradients of chemokines and cytokines that recruit immune cells or, alternatively, a few activated T cells could enter the inflamed area and in a paracrine manner, create the pro-inflammatory milieu themselves necessary to recruit and initiate other activated CD4+ T cells. On the other hand, T cell entry into areas of Aβ deposits has been observed to be beneficial in some cases[
91]. Primary cell line data indicated that Th2 cells inhibit Th1- and Th17-mediated toxicities by decreasing IL-1β and IL-6 production, suggesting that this subset has regulatory and anti-inflammatory capacities. Active immunization using Aβ42 in a mouse model of AD enhanced clearance of Aβ plaques[
92], and was thought to induce anti-inflammatory Th2 Teffs which increased neutralizing and clearing anti-Aβ antibodies. Therefore, to enhance Aβ clearance and downregulate the detrimental proinflammatory cascade in AD patients, an Aβ vaccine approach was thought a promising therapeutic strategy. However, after a successful phase 1 trial that immunized AD patients with Aβ1-42 peptide (AN1792) and QS21 adjuvant[
93], a phase 2a clinical trial yielded a proportion of patients that experienced subacute meningoencephalitis[
94]. Post-mortem evaluation of patients revealed that the vaccine had markedly cleared Aβ plaques, however neurofibrillary tangles remained[
95]. Moreover, T cell infiltration and inflammation near blood vessels were also observed in post-mortem tissues, suggesting that vaccination may generate T cells capable of infiltrating the CNS and exacerbating the pathology associated with AD.
Parkinson’s disease
PD is characterized by the progressive loss of dopaminergic neurons that originate within the substantia nigra (SN) and innervate the striatum resulting in the loss of dopamine, thus causing a majority of the motor symptoms associated with PD[
96]. Lewy bodies (LB) and Lewy neurites (LN), two hallmarks of PD, are intracellular inclusions consisting of modified and misfolded alpha-synuclein (α-syn) as well as ubiquitin[
97,
98]. These hallmarks present themselves in both sporadic and familial cases of PD. Familial PD accounts for approximately 10% of all PD cases and several genes have been identified in patients with a family history of PD. Six genes have been clearly linked to PD including
SNCA, LRRK2, PINK1, DJ-1, ATP13A2, and
Parkin[
99]. While the loss of neurons and dopamine explains the motor function disturbances, the underlying driving force behind the progression of PD is still unknown. However, works performed by many researchers provide strong evidence for the involvement of the immune system in PD and neurodegeneration.
Initial studies of peripheral lymphocyte populations from PD patients showed decreased frequencies and total numbers of CD4+ T lymphocytes compared to controls[
100‐
103]. Due to conflicting reports from only a few studies on T cell phenotypes, a firm consensus of other T cell subset changes in PD patients has proven difficult. For instance, the diminution of CD4+ T cell numbers in PD patients was found chiefly from decreased numbers of CD4+CD45RA+ naïve T cells and to a lesser extent from CD4+CD29+ memory subsets[
100], whereas, Stevens and colleagues reported decreased levels of CD4+CD45R0+ memory T cells[
103]. A recent study by Saunders and colleagues showed slight, yet significant increases in frequencies of CD4+CD45R0+ memory/effector T cells with concomitant diminution of CD4+CD45RA+ resting/naïve T cell levels[
102]. Additionally, frequencies of peripheral CD4+ T cells with effector-associated phenotypes such as FAS + were increased in patients, whereas those expressing α4β7 integrins and CD31 (PECAM1) were diminished. Notably, these changes in CD4+ T cell phenotypes were correlated with severity of motor function as scored by the Unified Parkinson’s Disease Rating Scale, part III (UPDRS III). Differences in these immunological profiles among the few reports may range from the heterogeneity of disease to individual laboratory methodologies, but clearly require further investigation to attain consensus profiles.
Post-mortem studies of PD patient brain tissues showed both CD4+ and CD8+ T cells in close proximity to dopaminergic neurons within the SN at levels exceeding 10-fold those found in brains of controls[
104]. Moreover, these levels of T cells were not detected in non-lesioned brain regions. Microarray analysis of peripheral blood leukocytes and SN brain tissue showed many genes expressed were in common with those expressed by Th17-mediated immune reactions and suggested to the authors that idiopathic parkinsonism is a Th17 dominant autoimmune disease[
105]. However, whether T cell infiltration is primary or secondary to PD progression is still unclear. Similarly, conflicting reports of Tregs in PD are also wrought with variances in levels detected ranging from increased frequencies in PD patients compared to controls to little or no differences[
13,
100‐
102,
106]. However, one study demonstrated the diminished capacity of Tregs from PD patients compared to those of controls to inhibit the proliferation of responder T cells from healthy donors[
102]. This suggested that a dysfunction in Tregs leads to a hyper-activated immune state and increased disease progression. The notion that hyper-activated immune responses support increased dopaminergic loss was provided by animal studies.
Multiple studies in animal models have demonstrated the involvement of the adaptive immune system in dopaminergic neurodegeneration using both active and passive transfer of immunity[
13,
104,
107]. In the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) mouse model, numbers of T cells in the SN are increased after intoxication, and interestingly, numbers of CD8+ T cells predominate those of CD4+ T cells. While in agreement of the relative proportions of T cell subsets within the SN of MPTP-treated mice, the total numbers of CD4+ T cells vary widely between studies. The importance of T cells to MPTP-induced neurodegeneration was found initially in adoptive transfer and reconstitution studies of functional T cells to immune deficient mice[
104,
108]. While both studies confirmed that immune deficient mice were not susceptible to MPTP intoxication, reconstitution of those mice with functional naïve lymphocytes partly restored MPTP susceptibility[
108] and CD4+ T cells were chiefly responsible for MPTP susceptibility[
104]. These studies point to a deleterious role of CD4+ T cells in PD, unlike the beneficial role they play as described in ALS; however in the former, those T cells were determined to be Th1 and Th17 effector T cells. Of primary importance to these studies was the finding that immune T cells could augment MPTP-induced neuroinflammation and neurodegeneration verified through the use of mice lacking CD4+ T cells[
104]. T cells from mice immunized with a modified self-antigen, nitrated α-synuclein (N-α-syn) recognized only N-α-syn, but not unmodified α-syn in
in vitro challenge assays. Moreover, N-α-syn specific Teffs exacerbated neuroinflammation and increased neuronal injury and subsequent neurodegeneration of dopaminergic neurons within the SN of MPTP mice[
108]. These findings indicate that N-α-syn, as a modified self-protein, either evades or breaks immunological tolerance to self α-syn and induces N-α-syn specific T cells. Indeed, by polarizing N-α-syn specific CD4+ T cells into different Teff types and adoptively transferring each separate Teff type into MPTP mice, another study showed that Th17 Teffs possess a significantly greater capacity to exacerbate dopaminergic neurodegeneration than the same number of Th1 Teffs[
13]. Together, these data indicate that CD4+ T cells play an important role in the neuroinflammation and subsequent neurodegeneration in models of PD and that Th17 Teffs are more potent at direct killing of neurons or alternatively, enhancing neurotoxic microglia. These data also support the notion that peripherally circulating Teffs, as found increased in PD patients, are capable of migrating to the sites of neuroinflammation and can exacerbate and accelerate PD disease progression.
Activated microglia and Teffs are thought to be mediators of neuroinflammatory processes in PD progression. Left uncontrolled, these mediators support an inflammatory cascade that affects the tempo of disease[
12]. Initially, studies directed to harness the inflammatory cascade demonstrated that adoptive transfer of CD4+ T cells from copolymer-1 (Cop-1) immunized donor mice protected dopaminergic nigral neurons and striatal termini in MPTP-treated mice[
109]. These observations supported the hypothesis that subpopulations of T cells mitigate neurodegeneration in the MPTP animal model of PD. These findings are congruent with known mechanisms by which Cop-1 regulates proliferative and inflammatory responses by preferentially inducing Th2, Th3, and Tregs that secrete anti-inflammatory cytokines[
12,
50,
51,
109,
110]. In a separate line of study, researchers found that CD4+CD25+ Tregs were most capable of suppressing neuroinflammation and neurodegeneration in the MPTP model with as few as 3.5 × 10
6 Tregs being sufficient to provide virtually complete neuroprotection to dopaminergic neurons along the nigrostriatal axis[
12]. Moreover, the degree of protection afforded by Tregs seems to increase with increasing inflammatory responses as evidenced by increased neuroprotection with Treg co-transfer with N-α-syn Th17 in the MPTP model[
13]. Moreover, use of vasoactive intestinal peptide (VIP), a known inducer of Treg activity[
99] increased the neuroprotective capability of Tregs from VIP-treated donors in the MPTP model[
13]. In that same vein, studies using granulocyte macrophage colony stimulating factor (GM-CSF) showed that treating animals with GM-CSF prior to MPTP-intoxication increased Treg activity in a dose dependent fashion as well as diminished the neuroinflammatory response and provided significant dopaminergic neuroprotection[
111]. Taken together, the results here and from PD patients formed the basis for a clinical strategy (ClinicalTrials.gov: NCT01882010) to target dysregulated Treg function in PD patients with GM-CSF (Leukine, sargramostim) to upregulate Treg numbers or function that will suppress neurotoxic Teff and microglial immune responses and afford a neuroprotective outcome that inhibits or slows PD progression[
2,
111].
As previously discussed, each neurodegenerative disease has different pathological hallmarks. The cellular location of these hallmarks varies from primarily intracellular in PD and ALS to primarily extracellular debris in MS and AD; however it should be noted that intracellular inclusions eventually become extracellular, especially upon neurodegeneration. Additionally, T cells generally do not recognize and respond to extracellular antigen and debris, but depend on the presentation of an antigen in the context of MHC or to bystander effects from glial cells. To our knowledge, no studies implicate different types of T cells or T cell responses in relation to both intracellular and extracellular pathological hallmarks. Thus, an interesting hypothesis asserts that the extent of external debris processed during disease progression could influence the overall scope of T cell responses. A most notable ramification of this notion is the putative importance that animal models do not present all the pathological hallmarks distinct for each disease. Nonetheless, animal models do provide researchers with the ability to assess pathology, etiology, and overall disease progression within the limits of the model, and represent indispensable tools to develop and test potential therapeutics.