Emerging Roles of T Helper Cells in Non-Infectious Neuroinflammation: Savior or Sinner

Abstract

CD4⁺ T cells, also known as T helper (Th) cells, contribute to the adaptive immunity both in the periphery and in the central nervous system (CNS). At least seven subsets of Th cells along with their signature cytokines have been identified nowadays. Neuroinflammation denotes the brain's immune response to inflammatory conditions. In recent years, various CNS disorders have been related to the dysregulation of adaptive immunity, especially the process concerning Th cells and their cytokines. However, as the functions of Th cells are being discovered, it's also found that their roles in different neuroinflammatory conditions, or even the participation of a specific Th subset in one CNS disorder may differ, and sometimes contrast. Based on those recent and contradictory evidence, the conflicting roles of Th cells in multiple sclerosis, Alzheimer's disease, Parkinson's disease, epilepsy, traumatic brain injury as well as some typical mental disorders will be reviewed herein. Research progress, limitations and novel approaches concerning different neuroinflammatory conditions will also be mentioned and compared.

Keywords: Th cells; alzheimer’s disease; epilepsy; mental disorders; multiple sclerosis; neuroinflammation; parkinson’s disease; traumatic brain injury (craniocerebral trauma).

Figure 1

Subsets, transcriptional regulators and key cytokines of Th cells. APCs activate naïve CD4⁺ T cells by presenting antigens. The activation also requires combination with costimulatory molecules, which triggers the production of polarizing cytokines and subsequent differentiation of naïve CD4⁺ T cells into distinct effector Th and Treg subsets. The polarized differentiations are characterized by lineage-specific regulators and the secretion of key cytokines. The early response of those T cells is regulated by STATs. STATs can further influence the expression of master transcription factors. Positive regulators are shown in black, while negative regulators are shown in red. Th cells, T helper cells; APCs, antigen presenting cells; Treg cells, regulatory T cells; STAT, signaling transducer and activation of transcription molecules; Ag, antigen; TCR, T-cell receptor; IL, interleukin; TGF-β, transforming growth factor β; TNF, tumor necrosis factor; Tfh cells, follicular T helper cells; T-bet, T-box transcription factor 21; ROR-γt, retinoic acid-related orphan receptor γt; Foxp3, forkhead box P3; IRF4, Interferon Regulatory Factor 4; IFN-γ, interferon γ.

Figure 2

Th1, Th17 cells and EAE susceptibility. IL-12 and IL-23 respectively promotes the differentiation of Th1 and Th17 cells. IL-12 is composed of p35 and p40 subunit, while IL-23 is composed of p19 and p40 subunit. Knock-out of p40 or p19 induced resistance to EAE in mice, yet p35^-/- mice showed high susceptibility to EAE. IL-17 is the signature cytokine secreted by Th17 cells. IL-17-dificient mice also showed resistance to EAE, which could be reversed by IL-1β or IL-17 treatment. Both MOG-specific Th1 and Th17 cells could induce EAE after being transferred to mice, yet their severities differ. Th, T helper; EAE, experimental autoimmune encephalomyelitis; IL, interleukin; MOG, myelin oligodendrocyte glycoprotein; KO, knock-out.

Figure 3

The two-wave theory of MS pathogenesis and the interactions between Th17 and other cells. (1) in the priming process, naïve T cells in the periphery become antigen-specific memory T cells. (2) those T cells infiltrate the blood-CSF barrier located in the choroid plexus. (3) after entering the subarachnoid space, Th17 cells undergo clonal expansion. (4, 5) the second wave denotes the activation of the BBB and recruitment of perivascular leukocytes. Plasma membrane molecules such as CCR6, CD6 and CD49d enables Th17 cells to cross BBB endothelium. Dendritic cells and macrophages could be recruited by GM-CSF secreted by Th17 cells. (6) Th17 cells contact neuron directly and lead to neuron damage via affecting intra-neuron Ca²⁺ concentrations. (7) Th17 cells could damage oligodendrocytes through direct contact or increased oxidative stress. (8, 9) various studies also demonstrated the effect of Th17 cells and their cytokines on astrocytes and neurons. GM-CSF could directly act on astrocytes and promote their recruitment. MS, multiple sclerosis; Th, T helper; CSF, cerebrospinal fluid; BBB, blood brain barrier; GM-CSF, granulocyte-macrophage colony-stimulating factor; APC, antigen-presenting cells; CNS, central nervous system.