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T regulatory cells; Tregs; Neuroinflammation; Immunosuppression; Autoimmunity; Neurological disorders; Cytokines

Introduction

The central nervous system (CNS), once considered an immunologically privileged site, is now recognized to be under constant surveillance by the immune system. While immune responses are essential for defending against pathogens and clearing cellular debris, dysregulated immune activity within the CNS can lead to neuroinflammation, contributing to the pathogenesis of various neurological disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), and stroke. T regulatory cells (Tregs), a specialized subset of CD4+ T cells characterized by the expression of the transcription factor Foxp3, play a crucial role in maintaining immune homeostasis by suppressing excessive immune responses and preventing autoimmunity. This review explores the current understanding of the role of Tregs in modulating neuroimmune responses, focusing on their mechanisms of action and their implications in neurological diseases. 

Results

Tregs exert their immunosuppressive functions through several distinct mechanisms. One key mechanism involves the production of immunosuppressive cytokines, such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β) [1]. IL-10 can inhibit the production of pro-inflammatory cytokines by other immune cells, such as microglia and macrophages, and promote their transition to an anti-inflammatory phenotype. TGF-β can suppress T cell proliferation and differentiation, and also promote the differentiation of naive T cells into Tregs. Another important mechanism of Treg suppression involves cell-to-cell contact. Tregs can express inhibitory molecules, such as CTLA-4 and PD-1, which can bind to ligands on other immune cells and inhibit their activation [2]. CTLA-4, for instance, can compete with CD28 for binding to B7 molecules on antigen-presenting cells (APCs), thereby inhibiting T cell activation. Tregs can also suppress immune responses through the consumption of IL-2, a growth factor essential for T cell proliferation [3]. By expressing high levels of the IL-2 receptor α chain (CD25), Tregs can deprive other T cells of IL-2, limiting their proliferation and activation. In the context of neuroinflammation, Tregs play a crucial role in suppressing excessive immune responses within the CNS. Studies have shown that Tregs can infiltrate the CNS and suppress the activity of autoreactive T cells that contribute to neuroinflammation [4]. In MS, for example, Tregs can suppress the proliferation and cytokine production of autoreactive T cells targeting myelin antigens, thereby reducing demyelination and axonal damage. In AD, Tregs can modulate microglial activation and reduce the production of pro-inflammatory cytokines, potentially slowing down the progression of neurodegeneration. In stroke, Tregs can reduce post-ischemic inflammation and promote neurovascular remodeling, contributing to improved functional recovery. The importance of Tregs in maintaining CNS homeostasis is further supported by studies showing that depletion or dysfunction of Tregs can exacerbate neuroinflammation and worsen disease outcomes in various neurological disorders. For instance, in experimental models of MS, depletion of Tregs leads to increased disease severity and more extensive demyelination. Conversely, adoptive transfer of Tregs can attenuate neuroinflammation and improve disease outcomes. Recent research has also focused on identifying specific factors that regulate Treg function in the context of neuroinflammation. Studies have shown that certain cytokines, such as IL-35, can enhance Treg suppressive activity [5]. Furthermore, specific transcription factors, such as Foxp3, are essential for Treg development and function [6]. Genetic variations in genes encoding these factors can influence Treg activity and susceptibility to neuroinflammatory diseases. The role of the gut microbiome in modulating Treg function and influencing neuroinflammation is also being increasingly recognized. The gut microbiota can influence systemic immune responses and subsequently impact neuroinflammation through various mechanisms, including the production of short-chain fatty acids (SCFAs) [7]. SCFAs can promote Treg differentiation and enhance their suppressive activity. Furthermore, studies have shown that environmental factors, such as stress and infection, can influence Treg function and susceptibility to neuroinflammatory diseases [8]. These factors can alter the balance between pro-inflammatory and anti-inflammatory responses, affecting Treg activity and their ability to suppress neuroinflammation. Recent studies have explored the therapeutic potential of targeting Tregs in neurological disorders. Strategies aimed at enhancing Treg function, such as adoptive transfer of ex vivo expanded Tregs or administration of IL-2, have shown promise in preclinical studies and some clinical trials [9]. Other approaches focus on promoting Treg induction or enhancing their suppressive activity through pharmacological interventions. For instance, low-dose IL-2 therapy has been shown to expand Tregs and improve clinical outcomes in some autoimmune diseases [10]. 

Discussion

The findings summarized in this review highlight the critical role of Tregs in modulating neuroimmune responses and maintaining CNS homeostasis. Tregs exert their immunosuppressive functions through multiple mechanisms, including the production of immunosuppressive cytokines, cell-to-cell contact, and consumption of IL-2. Dysregulation of Treg function can contribute to the pathogenesis of various neurological disorders. 

Conclusion

Tregs play a crucial role in controlling neuroinflammation and preventing autoimmunity within the CNS. Further research is needed to fully understand the complex mechanisms regulating Treg function in the context of neuroinflammation and to develop more targeted and effective therapeutic strategies based on modulating Treg activity for the treatment of neurological disorders.

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