T-cell-mediated regulation of neuroinflammation involved in neurodegenerative diseases

Abstract

Neuroinflammation is involved in several neurodegenerative disorders and emerging evidence indicates that it constitutes a critical process that is required for the progression of neurodegeneration. Microglial activation constitutes a central event in neuroinflammation. Furthermore, microglia can not only be activated with an inflammatory and neurotoxic phenotype (M1-like phenotype), but they also can acquire a neurosupportive functional phenotype (M2-like phenotype) characterised by the production of anti-inflammatory mediators and neurotrophic factors. Importantly, during the past decade, several studies have shown that CD4+ T-cells infiltrate the central nervous system (CNS) in many neurodegenerative disorders, in which their participation has a critical influence on the outcome of microglial activation and consequent neurodegeneration. In this review, we focus on the analysis of the interplay of the different sub-populations of CD4+ T-cells infiltrating the CNS and how they participate in regulating the outcome of neuroinflammation and neurodegeneration in the context of Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis and multiple sclerosis. In this regard, encephalitogenic inflammatory CD4+ T-cells, such as Th1, Th17, GM-CSF-producer CD4+ T-cells and γδT-cells, strongly contribute to chronic neuroinflammation, thus perpetuating neurodegenerative processes. In contrast, encephalitogenic or meningeal Tregs and Th2 cells decrease inflammatory functions in microglial cells and promote a neurosupportive microenvironment. Moreover, whereas some neurodegenerative disorders such as multiple sclerosis, Parkinson’s disease and Alzheimer’s disease involve the participation of inflammatory CD4+ T-cells 'naturally', the physiopathology of other neurodegenerative diseases, such as amyotrophic lateral sclerosis, is associated with the participation of anti-inflammatory CD4+ T-cells that delay the neurodegenerative process. Thus, current evidence supports the hypothesis that the involvement of CD4+ T-cells against CNS antigens constitutes a key component in regulating the progression of the neurodegenerative process.

Adaptive Immunity in Schizophrenia: Functional Implications of T Cells in the Etiology, Course and Treatment

“…An increasing body of evidence suggests pivotal roles of activated T cells in inflammatory and degenerative CNS disorders, and they are believed to actively contribute to neuronal damage (Brochard et al 2009;Gelderblom et al 2014;González and Pacheco 2014;Maxeiner et al 2009;Zhang et al 2013). Encephalitogenic inflammatory CD4+T cells such as Th1, Th17, GM-CSF producer CD4+ T cells and γδT-cells strongly induce chronic neuroinflammation.…”

“…It is now a well established fact that adaptive immunity in conjunction with innate immunity plays active role in brain development and function (Filiano et al 2014). The ability of T cells to infiltrate brain, activate microglia and induce neuroinflammation is a documented finding; such processes are known to impair higher order brain functions and also lead to neuroprogressive changes (Amor et al 2010;Engelhardt 2006;González and Pacheco 2014;Hickey et al1991).…”

Selective Targeting of T and B Cell Populations by Alemtuzumab in the Treatment of Multiple Sclerosis

“…7 • In the central nervous system (CNS), microglial cells produce pro-inflammatory cytokines such as tumour necrosis factor (TNF)-α, and cytotoxic substances such as reactive oxygen species and reactive nitrogen species that lead to neuro-inflammation and the direct destruction of neurons. 8 • CD8 'killer' T cells destroy axons; membrane damage in major histocompatibility complex class I restricted neurons by CD8+ T cells suggest granule-mediated death. [9][10][11] • Interleukin (IL)-10 producers including CD4+, CD25+ and regulatory T cells (Tregs) are able to suppress inflammation.…”

“…Tregs normally act to inhibit autoreactive cells. Numbers and functional capacity of Treg cells is impaired in patients with relapsing-remitting MS (RRMS), 8,12 which allows autoreactive T cells to induce CNS damage.…”

Lymphocytes reduce nigrostriatal deficits in the 6-hydroxydopamine mouse model of Parkinson’s disease

“…The pathogenic impact of the adaptive immune system has been far less explored in PD, although lymphocyte infiltration into the brain of PD patients has been described (McGeer et al 1988a;Brochard et al 2009). Because lymphocytes have been found to be crucial in the pathogenesis of other neurodegenerative diseases (e.g., multiple sclerosis, Alzheimer's disease) and in acute stroke (Goverman 2009;Kleinschnitz et al 2013;González and Pacheco 2014), this study aimed to investigate the role of the adaptive immune system in a widely-used toxic rodent model of PD by 6-hydroxydopamine (6-OHDA) injection into the nigrostriatal dopaminergic system. 6-OHDA toxicity is mediated by oxidative injury due to cytotoxic mediators such as hydrogen peroxidase, hydroxyl radicals and superoxide anions (Zigmond et al 1992) and impaired mitochondrial function (Kupsch et al 2014).…”