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Lin, C.;  Guo, J.;  Jia, R. Regulatory T Cell-Derived Extracellular Vesicles in Human Diseases. Encyclopedia. Available online: (accessed on 11 December 2023).
Lin C,  Guo J,  Jia R. Regulatory T Cell-Derived Extracellular Vesicles in Human Diseases. Encyclopedia. Available at: Accessed December 11, 2023.
Lin, Can, Jihua Guo, Rong Jia. "Regulatory T Cell-Derived Extracellular Vesicles in Human Diseases" Encyclopedia, (accessed December 11, 2023).
Lin, C.,  Guo, J., & Jia, R.(2022, November 28). Regulatory T Cell-Derived Extracellular Vesicles in Human Diseases. In Encyclopedia.
Lin, Can, et al. "Regulatory T Cell-Derived Extracellular Vesicles in Human Diseases." Encyclopedia. Web. 28 November, 2022.
Regulatory T Cell-Derived Extracellular Vesicles in Human Diseases

Regulatory T (Treg) cells play crucial roles in maintaining immune self-tolerance and immune homeostasis, and closely associated with many human diseases. Treg cells-derived extracellular vesicles (Treg-EVs) have been demonstrated as a novel cell-contact independent inhibitory mechanism of Treg cells. Treg-EVs contain many specific biological molecules, which are delivered to target cells and modulate immune responses by inhibiting T cell proliferation, inducing T cell apoptosis, and changing the cytokine expression profiles of target cells. The abnormal quantity or function of Treg-EVs is associated with several types of human diseases or conditions, such as transplant rejection, inflammatory diseases, autoimmune diseases, and cancers. Treg-EVs are promising novel potential targets for disease diagnosis, therapy, and drug transport. Moreover, Treg-EVs possess distinct advantages over Treg cell-based immunotherapies. 

regulatory T cells extracellular vesicles treatment diagnosis

1. Introduction

Regulatory T (Treg) cells are a special subpopulation of CD4+ T cells and are considered a vital regulator in maintaining immunological self-tolerance and immune homeostasis [1][2]. They are characterized by high expression of CD25 (cytokine IL-2 receptor alpha chain) and specific expression of transcription factor forkhead box protein P3 (FOXP3) [3][4][5][6][7]. Treg cells mainly develop in thymus-derived (tTreg cells or natural Treg cells, nTreg cells), but some Treg cells develop in the periphery (pTreg cells) [8]. Treg cells are involved in a variety of diseases, including autoimmune diseases, inflammatory diseases, transplantation rejection, and tumors [9]. Treg-mediated suppression can be attributed to contact-dependent or contact-independent mechanisms, such as expressing inhibitory receptors like cytotoxic T lymphocyte protein-4 (CTLA-4), CD39, and CD73 (Ecto-5-nucleotide enzyme), expressing perforin and granzyme B to kill target cells directly, the consumption of IL-2, and production of immunosuppressive cytokines (IL-10, IL-35, and TGF-β) [10][11][12][13][14]. Interestingly, numerous recent studies have demonstrated that Treg cells can release extracellular vesicles (EVs) to regulate target cells without direct contact with them [15][16][17][18].
Extracellular vesicles (EVs) are secreted by cells to the extracellular environment [19] and play a crucial role in intercellular communication by serving as vehicles for the transport of proteins, lipids, and nucleic acids [20]. EVs can be secreted by almost any cell type, including malignant cells and immune cells [21]. These vesicles play roles in antigen presentation, immune regulation, and signal transduction through autocrine and paracrine pathways, which are intimately related to the types of cells that release them [22]. According to vesicles’ sizes and production mechanisms, EVs can be divided into exosomes, micro-vesicles, and apoptotic bodies. Despite the mode of biogenesis being different, extracellular vesicle subtypes display a similar appearance, overlapping size, and standard composition [19]. The International Society for Extracellular Vesicles (ISEV) guidelines recommend using the operational terms for EV subtypes to replace the traditional classification [23]. In this entry,  the general term “extracellular vesicles” is mainly used based on the guidelines of MISEV2018.
Treg cells-derived extracellular vesicles (Treg-EVs) maintain self-immune tolerance and regulate immune responses by expressing specific molecules and delivering cargoes as a novel contact-independent mechanism of Treg cells.

2. The Cellular and Molecular Functions of Treg-EVs

2.1. Apoptosis

Treg-EVs can induce apoptosis in conventional T cells [24]. The EVs derived from some Treg cells can transfer miR-503 and iNOS enzyme to naïve T cells, block their cell cycle progression and induce apoptosis [25]. MiR-503 induces G1 cell cycle arrest by reducing the expression levels of cyclin E and cyclin D1 proteins in target cells [26][27]. iNOS enzyme can catalyze NO production and induce the downregulation of cyclin D1 and cell cycle arrest [28][29]. However, similar to cell proliferation, Treg-EVs may inhibit the apoptosis of some specific types of cells. In immortalized murine colonic epithelial cell line YAMC cells, Treg-EVs can inhibit apoptosis by transferring mir-195a-3p, which negatively regulates the apoptosis-related protein expression [30]. Interestingly, Treg-EVs show the indirect anti-apoptotic effects in vivo. Treg-EVs can inhibit apoptosis of myocardial cells in acute myocardial infarction mouse model by promoting M2 polarization of macrophage in myocardial tissues [31]. Therefore, the effects of Treg-EVs on cell apoptosis and proliferation depend on cell type.

2.2. Cytokine Production

Treg-EVs can significantly change the cytokine expression profile of target cells. In Teff cell, CD73 expressed on Treg-EVs inhibited the production of cytokines including IL-2, IL-6, and IFN-γ in a dose-dependent manner [16]. Moreover, Treg-EVs mainly transfer miRNAs to regulate cytokine production of target cells. Human Treg-EVs could increase the levels of IL-4 and IL-10 and decrease the levels of IL-6, IL-2, and IFN-γ in Teff cells by transferring miR-146a-5 and miR-150-5p [32]. Treg-EVs also preferentially package and transfer miRNA let-7d to Th1 cells and then suppress IFN-γ secretion by repressing Cox-2 expression [15]. In addition, Treg-EVs can transfer miR-142-3p to DCs and decrease IL-6 because the 3′ UTR of IL-6 is targeted by miR-142-3p [33].

2.3. Cell Differentiation

Treg-EVs can regulate target cell differentiation. EVs derived from TGF-β-induced CD4+ CD25+ Treg cells (iTreg) showed a significantly higher miR-449a-5p expression level than those from non-induced cells. iTreg-EVs inhibited Th17 differentiation by targeting the Notch1 pathway of T cells by transferring miR-449a-5 [34].

2.4. Cell Proliferation

Treg-EVs can inhibit cell proliferation via at least two ways. First, Treg-EVs inhibit target cell proliferation via surface proteins. Treg-EVs can suppress effector T (Teff) cell proliferation by CD73/CD39. CD73 (ecto-5′-nucleotidase) had been indicated to be the vital surface molecule of Treg cells-mediated inhibitory function. CD73 converts AMP to anti-inflammatory adenosine, which interacts with adenosine receptors A2aR expressed on effector T cells and then activates the intracellular cAMP pathway to inhibit cell proliferation [16]. CD39 expressed on Treg-EVs may inhibit Teff cell proliferation by the same mechanism [32]. Second, Treg-EVs can transfer miRNAs to target cells and suppress cell proliferation. For example, Human Treg-EVs inhibit CD4+ T cell proliferation by delivering miR-146a-5p, which down-modulates critical genes IRAK2 and STAT1 necessary for T cell proliferation [35]. In addition, Treg-EVs transfer let-7d to Th1 cell and inhibit cell proliferation [15]. However, Treg-EVs may promote cell proliferation in some specific types of cell, such as immortalized murine colonic epithelial cell line YAMC cells [30].

3. The Roles of Treg-EVs in Human Diseases

3.1. Transplantation Rejection

Recently, the roles of Treg-EVs in transplant rejection have significantly attracted the attention of researchers. At present, solid organ transplantation is still the first choice for treating end-stage organ failure. However, chronic immune rejection significantly limits the survival rate of the transplant. Patients have to take immunosuppressive drugs to prevent rejection in the long term, which often causes severe side effects. T regulatory cell-mediated transplantation tolerance is considered an attractive novel therapeutic strategy. Treg cells can reduce transplantation rejection by mediating immune suppression and maintaining immune tolerance [36][37]. Similar to Treg cells, Treg-EVs can also prevent transplantation rejection and prolong the survival time of transplant.

3.1.1. Kidney Transplantation

Treg-EVs, especially exosomes with a size of 30–100 nm, could inhibit T cell proliferation, delay acute rejection, and then significantly prolong the survival time of allografts in a rat kidney transplantation model [18]. Similarly, Treg-EVs could also prolong the survival time of kidney transplantation in a rat model of kidney allograft by inhibiting T cell proliferation [25].

3.1.2. Liver Transplantation

In a rat orthotopic liver transplantation (OLT) model, the injection of mouse natural CD4+ CD25+ Treg-EVs can significantly prolong the survival time of animals. Mechanically, Treg-EVs induced the cell cycle arrest in CD8+ cytotoxic T lymphocytes (CTLs) and then inhibited proliferation and cytotoxic activity by reducing the expression of perforin and IFN-γ, which play a crucial role in immune rejection [38].

3.1.3. Skin Transplantation

In a mouse model of humanized skin transplantation, human Treg-EVs prevented alloimmune mediated human skin allograft damage and prolonged skin allograft survival by limiting immune cell infiltration. Mechanically, Treg-EVs modified the cytokine production of Teff, such as reducing IL-6 while increasing IL-4 and IL-10 [32]. Blocking IL-6 production and IL-6 signaling pathway [39][40] and increasing IL-4 level [41] can promote transplantation tolerance.

3.2. Autoimmune Diseases

Autoimmune diseases can be attributed to the immune responses to self-antigens resulting in damage or dysfunction of tissues, which are often accompanied by abnormal quantity and/or function of Treg cells [42]. Abnormal Treg-EVs are associated with the pathogenesis of various autoimmune diseases.

3.2.1. Psoriasis

Psoriasis is a chronic, immune-mediated disorder manifesting in the skin and joints [43]. Treg cells are dysfunctional in most patients with psoriasis and play an important role in psoriasis pathogenesis. Treg-EVs may be associated with disease progression. The expression of multiple miRNAs derived from T cells was significantly upregulated in the sera of psoriasis patients compared with healthy donors. Interestingly, after treatment with etanercept (a tumor necrosis factor α (TNF-α) inhibitor biologic), the expression of miR-146a-5p enriched in Treg-EVs was increased, unlike other miRNAs that returned to normal levels. However, there is no direct evidence that miRNA changes in serum are associated with Treg-EVs. Therefore, the values of miRNAs derived from Treg-EVs in psoriasis need more extensive studies [35].

3.2.2. Multiple Sclerosis (MS)

Multiple sclerosis is an autoimmune disease characterized by axonal degeneration of the central nervous system [24][44]. The defects in the Treg function have been considered one of the possible mechanisms leading to MS [45][46]. Compared with normal human Treg-EVs, the ability of extracellular vesicles from MS patients to inhibit the proliferation and induce apoptosis of conventional T cells (Tconv) was significantly reduced. Mechanically, the dysregulation of immunomodulatory molecules related Treg-EVs might contribute to insufficient Treg cell activity in MS patients [24].

3.2.3. Rheumatoid Arthritis (RA)

Rheumatoid arthritis is an autoimmune disease characterized by synovial hyperplasia and irreversible destruction of articular cartilage [47]. Th17 cell expansion and impaired Treg function are associated with disease progression [48]. TGF-β-induced Treg cells-derived EVs (iTreg-EVs) preferentially localize to pathological joints and delay the occurrence of RA in a mouse collagen-induced RA experimental model. In this model, iTreg-EVs target the expression of the inflammatory gene Notch1 by transferring miR-449a-5p [34][49]. Notch signaling is involved in T cell development and differentiation, and inhibition of the Notch1 pathway could inhibit Th1 and Th17 cells, while promoting Treg cells. By transferring miR-449a-5p, iTreg-EVs reversed Th17/Treg imbalance to prevent disease progression and relieve RA symptoms [50][51].

3.3. Inflammation

Treg cells play key roles in suppressing inflammation, partially by releasing extracellular vesicles. Treg-EVs showed impressive roles in suppressing intestinal inflammation in animal models. Targeted inhibition of Th1 cell proliferation and IFN production by Treg-EVs is a possible mechanism to suppress inflammation. Let-7d deficient murine Treg-EVs failed to prevent colitis compared with wild-type Treg-EVs. The lack of Dicer (required for miRNA maturation) and Rab27 (required for vesicle release) or impaired transport of let-7d abolished the ability of Treg cells to suppress inflammation [15]. Let-7d of Treg-EVs targeting Cox-2 prevented Th1 cell-mediated intestinal inflammation [15][52].
In addition, Treg-EVs alleviate inflammatory bowel disease (IBD) by transferring miRNA to intestinal epithelial cells. IBD is a non-specific intestinal inflammatory disease with intestinal epithelial barrier dysfunction. In a dextran sodium sulfate (DSS)-induced IBD mouse model, Treg-EVs promoted the reparative process of intestinal epithelial barrier damage. Mechanically, Treg-EVs transferred miR-195a-3p to the intestinal epithelial cells, which directly targeted the mRNA of CASP12 gene, and negatively regulated the expression of Caspase 12, a pro-apoptotic protein. Therefore, Treg-EVs can promote intestinal epithelial cell proliferation and inhibit apoptosis and then reduce IBD symptoms [30].

3.4. Cancers

Treg-EVs may promote tumorigenesis via two ways. First, Treg-EVs inhibit cell proliferation of effector T cells [32] and cytokine production [15]. Moreover, Treg-EVs derived from natural CD8+ CD25+ regulatory T cells significantly inhibited DC-induced cytotoxic T lymphocyte responses and anti-tumor immunity in a mouse B16 melanoma model [17]. Second, the ability of Treg-EVs to promote the proliferation of immortalized epithelial cells [30] may also contribute to tumorigenesis. However, more studies are required to reveal the roles and mechanisms of Treg-EVs in tumorigenesis.

3.5. Other Diseases

Acute myocardial infarction (AMI) is an ischemic heart disease, and Treg cells can suppress the inflammatory response caused by myocardial infarction and promote pathological cardiac remodeling [53]. In an AMI mouse model, Treg-EVs reduced myocardial infarct size and myocyte cell apoptosis. The expression of iNOS (a marker of M1 macrophages), IL-1β, and TNF-α was notably suppressed in myocardial tissue treated by Treg-EVs. In contrast, Arg-1 (a marker of M2 macrophages) and TGF-β were significantly up-regulated. Interestingly, the depletion of mouse endogenous macrophages abolished the effects of Treg-EVs on AMI [31], suggesting that Treg-EVs may ameliorate AMI by promoting the polarization of macrophages to M2 style.

4. Application of Treg-EVs in Human Diseases

4.1. Transplantation and Autoimmune Diseases

Treg-EVs are a promising tool to treat immune-related diseases. Treg cells have been applied in the phase I/II clinical trials of patients with organ transplantation such as kidney transplantation (NCT02129881) [54] and liver transplantation (NCT02166177), as well as patients with autoimmune diseases such as autoimmune hepatitis (NCT02704338). However, the inflammatory environment may lead to human Treg cell instability and the phenotypic conversion of Treg cells into helper T cells (Th) such as Th1, Th2, and Th17 cells [55].
Like Treg cells, Treg-EVs may regulate immune responses, inhibit transplant rejection, and promote tissue regeneration. Recently, many types of EVs from mesenchymal stem cells (MSC), endothelial colony-forming cells (ECFC), neural stem cells (NSC), and other sources in regenerative therapy [56] have been used in pre-clinical and clinical studies. Therefore, Treg-EVs may be used to replace Treg cells for the treatment of inflammatory diseases directly. However, similar to other EVs, some technical issues must be solved before clinical application. It is a big challenge to isolate a large number of clinical-grade quality Treg-EVs under GMP conditions. Meanwhile, the technologies for the clinical-scale separation and in vitro expansion of Treg cells are also under development [56][57].

4.2. Biomarkers for Disease Diagnosis

Treg-EVs may be used as new and potential biomarkers for disease diagnosis. EVs are released by virtually all cell types in the body and have been widely found in various biofluids, including plasma [58], semen [59], urine [60], tumor effusions [61], and so on. More importantly, EVs express cell type-specific markers. The composition of EVs can reflect the physiological and pathological changes of cells or tissues from which EVs are derived, making the application of EVs possible as biomarkers for diagnosing diseases. The levels of EVs and the changes in their components such as proteins, miRNAs, and mRNAs can be used as diagnostic markers, closely correlated with the disease’s occurrence, development, and prognosis. The application of EVs as biomarkers in tumors [62], liver diseases [63], Parkinson’s disease [64], and other diseases has entered clinical research and has a large number of reviews.
As early as 2014, it was proposed that EVs derived from Treg cells could be used as a possible therapeutic and diagnostic tool in transplantation [57]. However, so far, Treg-EVs application has been limited in animal studies and not been used in clinical trials for several possible reasons, including the lack of standardized protocol for isolation and purification of Treg-EVs, as well as unified and standardized procedures for the analysis of Treg-EVs.

4.3. Delivery Media

As the messengers for intercellular communication, EVs can serve as the ideal carriers to transport therapeutic proteins, nucleic acids, and drugs to the target cells in clinical trials to treat diseases [65]. Treg-EVs can target a variety of cells, and the use of Treg-EVs for drug transport is a perfectly reasonable assumption after discovering EVs’ structural and functional features.
For example, the modified Treg-EVs can be used as a vehicle for the delivery of anti-VEGF antibodies (aV) to reduce choroidal neovascularization in both mouse and monkey models. The ocular neovascular disease is a progressive disease that can cause severe vision loss. Using antibodies targeting vascular endothelial growth factor (VEGF) is the most effective treatment. The rEXS–cL–aV, that is, Treg-EVs conjugated with aV using a peptide linker (cL), is a nanodrug. First, Treg-EVs enhance the delivery efficiency of aV. Conjugated aV transported by Treg-EVs accumulates in the neovascularization lesions. The ability of Treg-EVs to localize to neovascularization lesions, similar to the migration of Treg cells to sites of inflammation, might be attributed to the expression of chemokine receptors (such as CCR6) on Treg-EVs. Second, due to the slower elimination of Treg-EVs than that of soluble proteins, rEXS–cL–aV has prolonged the retention compared with aV alone. In addition, Treg-EVs mediate immunosuppression and synergize with aV to form a combination therapy. Treg-EVs contributed greatly to the high treatment efficacy of rEXS–cL–aV [66].
Obviously, in addition to the obstacles of Treg-EVs application mentioned above, the modification of EVs may generate additional difficulties. In fact, extracellular vesicle modification procedures may cause membrane damage, which may trigger the immune responses. Moreover, it is difficult to control the amounts of drugs loaded into EVs. In addition to simply mixing EVs with drugs to get hydrophobic compounds into EVs, commonly used methods include physical or chemical induction, which have their limitations. At present, studies have shown that the use of different routes of administration causes EVs to have different biodistribution patterns in the human body. Therefore, formulating an appropriate dosage regimen must also be considered [67]. Nonetheless, Treg-EVs as a drug-delivery system are a promising avenue for treating human diseases.


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