It has not yet been established how brain senescence is influenced by aging of other body tissues. However, recently, several studies have reported that circulating immune cells are involved in brain senescence. Aging mice and humans show increased type I interferon (IFN) response at the CP, and the neutralization of the aging-induced type I IFN response restores CP function in the brain, partially restoring cognitive function and hippocampal neurogenesis [9]. Although circulating immune cells from young blood did not directly affect brain function in aged CP (type I IFN response), this study suggests that targeting the CP, which is the major gate for circulating immune cells, might ameliorate cognitive decline in aging. In addition, a different study reported that young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice [10]. Supply of young blood using the heterochronic parabiosis model in aged mice stimulates adult neurogenic processes, oligodendrocyte activity, synaptic plasticity, and vascularization in the aged CNS [11]. Although the mechanism by which youthful blood-borne factors access the aged CNS is still unclear, it can be speculated that youth-associated leukocytes or youthful systemic factors seem to be associated with restoration of CNS functional decline with age.

Alzheimer disease (AD) is characterized by the accumulation of amyloid beta (Aβ), and the impaired elimination of this neurotoxic peptide contributes to disease progression [12]. Cerebral amyloid angiopathy, a condition involving Aβ deposition within the cerebral vasculature, is also observed in most patients with AD. A clearance system exists within the CNS to prevent accumulation of toxic peptides, and this system is regulated by innate immune cells called microglia. Microglia modulate inflammatory reactions, phagocytize neuronal debris and foreign pathogens, and induce wound healing [13]. Thus, many studies have focused on the function of microglia in AD. Interestingly, however, it has been shown that circulating monocytes play a role in the elimination of Aβ in AD [14]. Live intravital two-photon microscopy showed that patrolling monocytes are attracted to and crawl onto the luminal walls of Aβ-positive veins, but not on Aβ-positive arteries or Aβ-free blood vessels [14]. Crawling monocytes carried Aβ in these veins and were able to circulate back into the bloodstream. These data clearly showed that enhancing the function of specific circulating monocytes by boosting the immune system constitutes a potential therapeutic target in AD.

Parkinson disease (PD) is a chronic progressive disorder that is characterized by tremor, rigidity, and bradykinesia. PD is caused by degeneration of the nigrostriatal pathway, which consists of both dopaminergic (DA) and nondopaminergic neurons [15]. The pathological hallmarks of PD are loss of nigrostriatal DA neurons and formation of Lewy bodies, which are aggregates of proteinaceous cytoplasmic inclusions [16]. Degeneration of DA neurons is accompanied by activation of microglia and infiltration of T lymphocytes into the CNS [17]. Mouse strains that lack T cells or mature T cells are relatively resistant to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced degeneration of DA neurons [18]. Notably, CD4⁺ T cells, but not CD8⁺ T cells, are involved in the MPTP resistance [19]. Collectively, these data indicate that the deleterious activity of MPTP is associated with infiltrating CD4⁺ T cells. Further, passive transfer of T cells obtained from mice immunized with the immunomodulatory drug glatiramer acetate is neuroprotective against MPTP neurotoxicity, possibly by increasing anti-inflammatory cytokines such as interleukin (IL)-4, IL-10, and transforming growth factor-beta [20,21].

Regulatory T cells (T_reg cells), a specialized T-cell subtype, can be neuroprotective [21]. In vitro, T_reg cells suppress the inflammatory microglial phenotype, whereas CD4⁺ CD25^– effector T cells (T_eff cells) exacerbate the inflammatory microglial phenotype [22]. In an in vivo PD model, adoptive transfer of activated T_reg cells, but not T_eff cells provided neuroprotective effects in MPTP-induced DA cell loss [23]. These studies demonstrate that T cells are important participants in mediating cytotoxicity and neuroprotection in models of PD, depending on their subtype and microenvironment. Therefore, novel therapeutic approaches are needed to clarify the role of innate and adaptive immune responses in patients with PD.

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig disease, is a neurodegenerative disorder characterized by fatal progressive motor neuron death, consequently resulting in death within 3–5 years [24]. There is no effective therapeutic regimen, and several clinical trials using various types of stem cells as well as new chemical drugs are ongoing [25,26]. Neuroinflammation similar to other neurodegenerative diseases is one of the most striking hallmarks of ALS [27], a heterogeneous disease with various genetic backgrounds [28,29]. Recent studies have demonstrated that innate and adaptive immune cells play interdependent roles in regulating the rate of disease progression in ALS [30]. T lymphocytes, a type of adaptive immune cell, are able to infiltrate into the spinal cord in patients with ALS, and in an ALS mouse model, CD4⁺ T lymphocytes slowed disease progression, shaped microglial phenotypes, and extended survival [31,32]. ALS patients with elevated peripheral T_reg cell levels exhibited slow disease progression in a prospective cohort study, suggesting that T_reg cells may be associated with the slowing of ALS progression [30,33]. Because neuroinflammation is a prominent pathological feature in ALS, up-regulating T_reg cell activity or increasing the T_reg cell ratio in the immune system of patients with ALS may represent a potential therapeutic strategy.

Major depression exhibits various disease courses with inconsistent response to antidepressant treatments [34]. Despite the availability of both pharmacological and psychotherapeutic treatments to a large number of patients, major depression has high rates of relapse and recurrence. A long course of treatment is required for complete recovery from symptoms and prevention of relapse, which is considered the major obstacle in the treatment of major depressive disorder [35].

Most antidepressants were developed based on the “monoamine theory,” which postulates that persistent reduction in the levels of serotonin, norepinephrine, and dopamine in the synaptic cleft induces neuroplastic changes, inhibits neurogenesis, and affects cognitive function, finally leading to depression. Thus, current antidepressants are designed to elevate monoamines in CNS. However, more than 50%–70% of patients who recover from a first episode of depression are vulnerable to stress and are at risk of chronic depression [35,36]. In addition, more than 50% of patients are resistant to antidepressant treatment [35,36]. Thus, new approaches beyond the monoamine theory are needed to better treat depression.

Systemic inflammation is associated with the lack of clinical therapeutic benefit of antidepressants in patients resistant to treatment [37,38]. In addition, recent studies have demonstrated that the peripheral immune system is involved in susceptibility or resilience to social stress [39]. In an animal study, mice receiving IL-6 knockout bone marrow transplantation after irradiation were resilient to social stress, suggesting that the peripheral immune system interacts actively with the CNS to shape synaptic circuits [39]. Nude mice, which are T cell depleted, exhibit stress vulnerability, showing depressive-like behaviors in a single foot shock session [40]. Peripheral IL-4/10, an anti-inflammatory cytokine, prevents stress vulnerability in depressed mice via restoration of alternatively activated microglia phenotype [40]. The kynurenine pathway has been demonstrated as a factor linking “cytokine theory” and “monoamine theory” in depression, since pro-inflammatory cytokines lead to tryptophan degradation by indoleamine 2,3-dioxygenase and its metabolites with downstream enzymes inducing neurotoxicity, eventually resulting in depression [41]. Regarding the role of the innate immune system in the CNS, recent studies have demonstrated the role of microglia in depression [42]. Several data suggest that microglia are involved in brain homeostasis processes, such as synaptic transmission and neural plasticity, as well as in pathological brain processes [43]. Microglia interact closely with the peripheral immune system in healthy and diseased states [44]. Peripheral immune cells such as T_reg and Th2 cells and their releasing factors restore microglia functional phenotype in depressed mice, leading to reduced stress vulnerability [40]. Thus, targeting the circulating immune system could be an alternative therapeutic strategy, especially in recurrent and refractory forms of depression.

Schizophrenia is disabling neuropsychiatric disorder, characterized by positive symptoms (hallucinations and delusions), depression-like negative symptoms, cognitive dysfunction, and neurodegeneration [45,46]. Epidemiological and genetic studies strongly implicate neuroinflammation and peripheral immunity in the pathogenesis of schizophrenia [46-48]. Crosstalk between the peripheral immune system and the brain has been investigated extensively in the context of schizophrenia pathophysiology [49]. Recent population-based longitudinal studies and meta-analysis show an association between elevated levels of pro-inflammatory cytokines and the risk of psychosis [46-48]. In addition, malfunctions of both the innate and adaptive immune systems are observed in schizophrenia. As mentioned above, it is now well established that adaptive immunity in conjunction with innate immunity plays an active role in brain development and homeostasis. Recently, neurodegeneration has been demonstrated to be one of the predominant underlying mechanisms in schizophrenia progression, in which immunemodulatory processes play a crucial role [50]. For example, T-cell-related molecular changes in immune dysfunction have been demonstrated in patients with first-onset schizophrenia [51], and activated lymphocytes in the CSF and hippocampus of patients have been reported, suggesting BBB impairment [52]. Altogether, these studies indicate that T-cell-mediated immunity is involved in schizophrenia pathogenesis [53].