Background: Allergy represents a major health problem of increasing prevalence worldwide with a high socioeconomic impact. Our knowledge on the molecular mechanisms underlying allergic diseases and their treatments has significantly improved over the last years. The generation of allergen-specific regulatory T cells (Tregs) is crucial in the induction of healthy immune responses to allergens, preventing the development and worsening of allergic diseases. Summary: In the last decades, intensive research has focused on the study of the molecular mechanisms involved in Treg development and Treg-mediated suppression. These mechanisms are essential for the induction of sustained tolerance by allergen-specific immunotherapy (AIT) after treatment discontinuation. Compelling experimental evidence demonstrated altered suppressive capacity of Tregs in patients suffering from allergic rhinitis, allergic asthma, food allergy, or atopic dermatitis, as well as the restoration of their numbers and functionality after successful AIT. Key Message: The better understanding of the molecular mechanisms involved in Treg generation during allergen tolerance induction might well contribute to the development of novel strategies for the prevention and treatment of allergic diseases.

Allergy represents a major health problem of increasing prevalence worldwide, significantly affecting the patients’ and caregivers’ quality of life, especially within the most severe phenotypes. The propensity to develop allergies is influenced by genetic risk factors, environmental factors, and lifestyle [1‒3]. In clinical practice, the main manifestations of allergic diseases are allergic rhinitis (AR), asthma, food allergies, and atopic dermatitis (AD). Although different pheno-endotypes have been described, allergic diseases are mainly considered as a type 2-mediated inflammatory disease characterized by the production of high levels of IgE against innocuous stimuli known as allergens [1, 4]. The immunological basis of allergic diseases, mediated by innate and adaptive immune responses, involves two different and consecutive stages: the sensitization phase and the re-exposure phase, the latter comprising both early acute and late events [4‒6]. Failure to diagnose allergy and the lack of early interventions might well lead to disease progression, multi-morbidities, and uncontrolled diseases, which are associated to higher healthcare and personal costs. Therefore, there is an urgent need to enhance our understanding of the mechanisms underlying allergic diseases as well as to develop safer and more efficacy therapies able to improve current ones such as allergen-specific immunotherapy (AIT) or biological treatments [7, 8].

Non-allergen-specific therapeutic strategies have been developed in the last decades. Among them, biologicals such as monoclonal antibodies (mAbs) against specific key targets in the development of allergy stand out [8, 9]. Despite their demonstrated safety and clinical efficacy for many severe allergic patients, more research is still needed to confirm whether certain biologicals could display disease-modification capacity to prevent the onset or the progression of the allergic diseases [8]. Up to date, AIT remains the only treatment with potential long-term disease-modifying capacity for allergic diseases [10‒12]. Successful AIT is associated with a rapid desensitization of effector cells (mast cells and basophils) and apoptosis of T helper (Th) 2 cells. Then, the induction of allergen tolerance requires the generation of tolerogenic innate immunity, the inhibition of type 2-mediated responses, which require increasing Th1 cells, and the generation and maintenance of allergen-specific functional regulatory T (Tregs) and B (Bregs) cells [10, 13]. Functional allergen-specific Tregs are essential to achieve tolerance induction after successful AIT. Several studies have demonstrated that Tregs prevent and inhibit ongoing inflammation in allergy via several major pathways, displaying a key role both in the misbalance leading to the undesired reaction against allergens as well as in the inhibition of inflammatory responses after treatment discontinuation [13‒15]. In this article, we comprehensively review the current knowledge on the role played by Tregs in the context of AR, allergic asthma, food allergy, and AD as well as the potential application of this knowledge for the development of better biomarkers and therapeutic strategies for allergic diseases.

Tregs are a heterogeneous subset of CD4+ T cells with suppressive capacity that are essential for the maintenance of immune homeostasis and peripheral tolerance, thus playing a key role in preventing autoimmune and allergic diseases. Tregs are characterized by the expression of high levels of the α-subunit IL-2 receptor (CD25), the lack of the expression of the IL-7 receptor α-subunit (CD127), and the expression of the transcription factor forkhead box 3 (FOXP3), the master regulator of their development, function, and stability. Tregs can be generated and matured in the thymus upon self-antigen recognition, termed thymus-derived Tregs (tTregs), or in specialized peripheral tissues, constituting peripherally derived Tregs (pTregs) [15, 16].

The generation of tTregs occurs during thymic selection [17, 18]. After positive selection, thymocytes expressing T-cell receptors (TCR) with high affinity for self-antigens can undergo clonal deletion or differentiate into Tregs or effector CD4+ T cells. At early stages of thymic selection, agonist signaling stimulated by TCR and CD28 co-stimulatory ligands induces clonal deletion due to the expression of the proapoptotic Bim protein in autoreactive thymocytes. At late stages, the agonist signaling reduces the expression of the proapoptotic Bim protein, thus preventing death of agonist-signaled thymocytes and inducing CD25+ precursors. The persistence of late agonist signaling in the CD25+ precursors contributes to the generation of effector CD4+ T cells, whereas disruption of late agonist signaling by transforming growth factor (TGF)-β promotes the generation of mature tTregs (Fig. 1) [19, 20]. This Treg subset is predominant in bloodstream and in lymph nodes.

Fig. 1.

Origin and development of Tregs. Tregs can be generated in the thymus upon self-antigen recognition (tTregs) or in peripheral tissues from naïve CD4+ cells after the recognition of exogenous antigens (pTregs). During thymic selection, autoreactive thymocytes can undergo clonal deletion or can differentiate into CD25+ precursors, which generate effector CD4+ T (Teff) cells or tTregs due to TGF-β signaling. In the periphery, naïve CD4+ T cells can differentiate into pTregs, including iTregs, IL-10-producing Tregs (Tr1), and TGF-β-producing T helper 3 (Th3) cells. Both tTregs and pTregs suppress effector T-cell responses.

Fig. 1.

Origin and development of Tregs. Tregs can be generated in the thymus upon self-antigen recognition (tTregs) or in peripheral tissues from naïve CD4+ cells after the recognition of exogenous antigens (pTregs). During thymic selection, autoreactive thymocytes can undergo clonal deletion or can differentiate into CD25+ precursors, which generate effector CD4+ T (Teff) cells or tTregs due to TGF-β signaling. In the periphery, naïve CD4+ T cells can differentiate into pTregs, including iTregs, IL-10-producing Tregs (Tr1), and TGF-β-producing T helper 3 (Th3) cells. Both tTregs and pTregs suppress effector T-cell responses.

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pTregs are generated in the periphery from naïve CD4+ T cells after the recognition of foreign antigens from exogenous sources such as microbiota products, dietary antigens, or allergens, as well as self-antigens not encountered during thymic selection (Fig. 1) [21]. Therefore, the TCR repertoires of tTregs and pTregs are largely nonoverlapping. Strong TCR signaling, low co-stimulation, and high levels of TGF- β or retinoic acid favor the generation of pTregs in peripheral tissues [22]. pTregs can be further classified into peripheral induced FOXP3+ Tregs (iTregs), interleukin (IL)-10-producing Tregs (Tr1) [23], and TGF-β-producing Th3 cells [24]. These pTregs are particularly enriched in the intestines and the airways where they contribute to tolerance induction to environmental antigens such as allergens. In the intestine, several factors including retinoic acid, TGF-β, short-chain fatty acids, or microbiota metabolites promote the generation of pTregs. In the lung, CD103+FOXP3+ Tregs control immune responses to infections and restrict allergic responses through the suppression of Th2 responses [25]. Dendritic cells (DCs) are professional antigen-presenting cells that play a key role in the generation of pTregs. Immature or mature DCs conditioned by pathogen-derived molecules, FOXP3+ Tregs, and exogenous signals such as vitamin D3 metabolites [26], adenosine, histamine [27, 28], retinoid acid, mannan [29, 30], cannabinoids [31‒34], or heparan sulfate-related proteoglycan [35], promote the generation of Tregs through mechanisms involving soluble molecules such as TGF-β, retinoic acid, the enzyme indoleamine 2,3-deoxygenase (IDO), and surface-binding co-stimulatory molecules such as programmed death ligand 1 or inducible co-stimulatory molecule ligand. In addition, plasmacytoid DCs (pDCs) might well display intrinsic tolerogenic capacity to promote Tregs [36].

Other Treg populations have been identified, including CD8+ Tregs [37, 38] and double negative CD4CD8 TCRαβ+ [39, 40], which are involved in the prevention of transplant rejection and autoimmune diseases; TCRγδ Tregs, which are involved in the inhibition of immune response in tumors [41, 42]; or follicular Tregs (TFR), which are derived from tTregs, are characterized by the expression of C-X-C chemokine receptor (CXCR)5 and play a critical role in suppressing both follicular helper T (TFH) cell and B cell responses in the germinal center of secondary lymph tissues [43‒45].

In terms of differentiation, human blood Tregs can be subdivided into three populations by their different expression levels of FOXP3 or CD25 and CD45RA: CD45RA+FOXP3lowCD25low naïve/resting Tregs (fraction I); CD45RAFOXP3highCD25high effector Tregs (fraction II), which are generated from naïve Tregs upon TCR stimulation and display high suppressive capacity; and CD45RAFOXP3lowCD25low non-Tregs (fraction III), which barely exhibit suppressive activity and instead produce proinflammatory cytokines [46]. Although the majority of T cells of fraction III are not Tregs, CXCR5+ TFR are included in this heterogeneous group [15, 46, 47]. Recently, single-cell transcriptomic analysis separate Tregs into naïve, activated and effector Tregs, which include HLA-DRhigh, LIMS1high, highly suppressive FOXP3high, and highly proliferative MKI67high effector Tregs [48]. Duhen et al. [49] described new populations of memory Tregs that mirror the classical CD4+ Th cells, named Th-like Tregs. The Th-like Tregs express chemokine receptors CXCR3, C-C chemokine receptor (CCR)6, and CCR4 that are typically expressed by T-bet+-Th1, ROR-γt+-Th17, and GATA3+-Th2 cells, respectively. The shared homing receptor distribution origins the appropriate co-localization of Tregs and Th cells in peripheral tissues, allowing each subset of Tregs to suppress specific Th cell responses [50].

Although several cell types are implicated in the suppression of innate and adaptive immune responses, Tregs expressing CD4, CD25, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and FOXP3 are the key mediators involved in tolerance induction and homeostasis. The development, function, and stability of Tregs are determined by the high expression of FOXP3. In humans, patients with FOXP3 loss of function mutations develop immunodeficiency, polyendocrinopathy, and enteropathy X-linked syndrome which is characterized by autoimmunity and severe allergic inflammation including AD, eosinophilia, and increased serum IgE levels [51, 52]. Similarly, scurfy mice, an X-linked recessive murine mutant, lack Tregs and display severe systemic inflammation, autoimmune disorders, and allergic inflammation [53].

Recent studies have been focused on the molecular mechanisms involved in the development and function of Tregs, specifically at transcriptional and epigenetic level. The stable Treg phenotype and function depend on the dynamics of specific transcription factors and epigenetic changes, which begin to be stablished in early stages during thymic Treg differentiation. In addition to the promoter, different conserved noncoding sequences (CNS) have been identified at the FOXP3 gene locus, which have been identified as key functional enhancer elements for induction and stabilization of FOXP3 expression [54, 55]. CNS1 contains the TGF-β response element and participates in extrathymic Treg generation [56]. CNS2 is responsible for the stability of FOXP3 expression [57, 58]. CNS3 and the promoter-upstream CNS0 cooperatively initiate and maintain FOXP3 expression [59, 60]. DNA methylation is the most important Treg-specific epigenetic signature, which is generally associated with transcriptional repression. Therefore, Tregs display hypomethylation at FOXP3 gene loci but also at other Treg-associated genes such as CD25 and CTLA-4. Demethylation of CpG sites at CNS2 in FOXP3 gene facilitates the binding of transcription factors such as RUNX1 or FOXP3 itself, contributing to sustained expression of FOXP3 in tTregs. DNA demethylation in this site is also observed in pTregs but with a slightly reduced penetrance [57, 58, 61‒63]. It has been reported that ten-eleven translocation family are involved in CpG demethylation at CNS2 in Tregs [64, 65]. Fully methylation at CNS2 has been described to avoid abnormal FOXP3 induction in non-Tregs [62]. Histone methylation also activates or represses gene expression depending on the modified residue and the number of methyl groups incorporated. tTregs display unique H3K4me3 and H3K27me3 islands in comparison to effector CD4+ T cells [66]. Histone acetylation is another important chromatin modification in Tregs. Acetylation leads to a more open chromatin, enabling DNA binding, whereas histone deacetylation is associated with condensed chromatin and transcriptional inhibition. Histone acetylation together with hypomethylation opens chromatin, regulating the expression of Treg genes [67‒70]. Specifically, H3K27ac mark at FOXP3 promoter occurs in Tregs, and it facilitates and maintains FOXP3 expression [63, 71].

Tregs suppress different immune cell populations to reduce excessive inflammation and promote homeostasis. Tregs are able to suppress Th cells, B cells, neutrophils, basophils, eosinophils, mast cells, inflammatory DCs, and specific inflamed tissue cells. Tregs exert their suppressive functions by different mechanisms, such as the cell-to-cell contact, secretion of inhibitory cytokines, cytolysis, and metabolic disruption [13]. Contact-dependent Treg-mediated suppression includes the binding of CTLA-4 to co-stimulatory molecules CD80/CD86 on the DCs reducing their expression [72]; the elimination of antigen-MHC-II from DC surface by trans-endocytosis reducing antigen presentation [73]; the CTLA-4-mediated increase in IDO expression on DCs, which reduces the levels of tryptophan necessary for T effector cell proliferation [74]; the interaction of lymphocyte-activation gene 3 (LAG-3) with MHC-II, leading to suppression of DC maturation [75]; and the interaction of programmed cell death protein 1 (PD1) with programmed death ligand 1 on T- and B-cell population, resulting in the suppression of their functions [76]. Tregs secrete the immunoregulatory cytokines TGF-β, IL-10, and IL-35. These cytokines suppress the activation and proliferation of effector T and B cells and induce the generation of pTregs and Bregs [13]. Perforine-granzyme cytolysis is another important suppression mechanism by which Tregs can induce apoptosis in target cells such as CD4+ and CD8+ effector T cells [77]. The enzymes CD39 and CD73 on Treg surface act in tandem to degrade ATP to adenosine, an immunosuppressive purine nucleoside that inhibits DC antigen presentation and suppresses the proliferation of effector T cells through adenosine A2A receptor [78]. Tregs constitutively express CD25, the high-affinity IL-2 receptor, which bind to and deplete IL-2 from the environment, thus reducing its availability to effector T cells [79] (Fig. 2). Tregs play also a very important role in tissue repair and regeneration of muscle, bone, lung, and central nervous system [80] by mechanisms that include growth factor production (amphiregulin), induction of stem cell proliferation and differentiation, or inhibition of neutrophil and monocyte extravasation [80‒82].

Fig. 2.

Molecular mechanisms of Treg suppression. Tregs control innate and adaptive immune responses by different mechanisms, including cell-to-cell contact (CTLA-4 and LAG-3), secretion of inhibitory cytokines (TGF-β, IL-10, and IL-35), cytolysis (perforine-granzyme), and metabolic disruption (CD25, CD39, CD73). A2AR, adenosine A2A receptor; ATP, adenosine triphosphate; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DC, dendritic cell; IDO, indoleamine 2,3-deoxygenase; LAG-3, lymphocyte-activation gene 3; Teff, effector T cell; TGF-β, transforming growth factor β; Treg, regulatory T cell.

Fig. 2.

Molecular mechanisms of Treg suppression. Tregs control innate and adaptive immune responses by different mechanisms, including cell-to-cell contact (CTLA-4 and LAG-3), secretion of inhibitory cytokines (TGF-β, IL-10, and IL-35), cytolysis (perforine-granzyme), and metabolic disruption (CD25, CD39, CD73). A2AR, adenosine A2A receptor; ATP, adenosine triphosphate; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DC, dendritic cell; IDO, indoleamine 2,3-deoxygenase; LAG-3, lymphocyte-activation gene 3; Teff, effector T cell; TGF-β, transforming growth factor β; Treg, regulatory T cell.

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In the field of allergy, allergen-specific Tregs play a fundamental role in the induction and the maintenance of immune tolerance to allergens. However, the mechanisms by which Tregs are unable to maintain allergen tolerance in allergic patients are not yet completely understood.

Tregs in AR

AR is one of the most prevalent allergic diseases, affecting 5–15% of children and approximately up to 50% of adults [6]. According to the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines, AR is an IgE-mediated reaction to inhaled allergens including pollens, house dust mites, and animal allergens among others. It can be categorized as intermittent or persistent, and mild or moderate to severe [6]. The primary symptoms encompass itching, sneezing, runny nose, and nasal congestion. These symptoms, along with fatigue, frustration, and alterations of daily activities, sleep, and concentration, significantly impair the patient’s quality of life [6]. Additionally, AR often coexists with asthma and/or conjunctivitis [83, 84]. Genetic factors, along with inhaled allergens, play a significant role in the development of AR [6]. The pathophysiology of AR involves inflammation in the nasal mucosal mediated by the activation of type 2 innate lymphoid cells, DCs, Th2 cells, TFH cells, TFR cells, B cells, mast cells, basophils, eosinophils, as well as epithelial cells [4, 85].

As previously described, Tregs have the ability to control and inhibit the progression of allergen-specific immune reactions [4, 13]. However, different studies have reported that patients with AR display a decreased number of circulating FOXP3+ Tregs compared to healthy controls [86‒89] and an impaired in vitro suppressive capacity of Th2 responses [90]. Reduced expression levels of FOXP3 within the nasal mucosa have been reported [91‒93], which can be correlated with the severity of AR [86]. Of note, genetic analysis has demonstrated that certain polymorphisms of FOXP3 are associated with AR, which can impair Treg function, favoring allergic responses [94]. Immunoglobulin-like transcript 3 (ILT3) inhibits Treg function by regulating protein kinase CK2. Consequently, ILT3+ Tregs showed a reduced suppressive capacity and FOXP3 expression [95]. It has been reported that the frequency of ILT3+ Tregs is higher in AR patients than in healthy controls [96]. Additionally, the frequency of circulating IL-10-producing Tr1 cells as well as IL-35-inducible Tregs (iTr35, IL-35+CD4+CD25+FOXP3-) with suppressive capacity was decreased in patients with AR [97, 98]. Patients with AR also present a low number of CD8+CD25+CD137+ Tregs not only in peripheral blood but also in the nasal mucosa [99]. Moreover, a reduction in frequency of TFR cells in tonsils and peripheral blood was reported in patients with AR [100]. In contrast, the percentage of FOXP3- IL-17-A-producing Tregs was increased in AR population compared to healthy controls [101].

MicroRNAs (miR) are small endogenous RNAs that posttranscriptionally regulate mRNA expression of target genes. Their expression in Tregs in AR can be either up- or downregulated, thus influencing the cell function. This could be associated with the course of the disease [102]. In children with AR, purified Tregs exhibited significantly lower levels of miR-155 and miR-181a compared to healthy children. The miR-155 promoted Treg differentiation and proliferation through SOCS1 and SIRT1 pathways, while the miR-181a is involved in IL-10 and TGF-β production through PI3K/Akt pathway [103]. Consequently, the miR-181a could prevent the Treg/Th17 imbalance implicated in the pathogenesis of AR [104]. In contrast, other study has reported a high expression of the miR-202-5p in circulating Tregs of AR patients impairing Treg differentiation and function [105].

Some studies have investigated the role of Notch signaling pathways in Th2 cell differentiation in the context of AR. Remarkably, increased levels of Notch1 have been observed in AR patients compared to healthy controls, which positively correlated with the severity of AR and serum IgE levels [106]. Moreover, the inhibition of Notch1 signaling increased FOXP3 expression, leading to enhance Treg induction [106, 107]. Interestingly, a recent study has reported a downregulation of Notch2 expression in Tregs in the nasal mucosa of AR patients, with a correlation with the grade of allergy. Notch2 signaling pathway promoted the FOXP3 expression and reduced allergic inflammation [91].

Compelling experimental evidence demonstrates reduced numbers of Tregs and impairs suppressive capacity in AR, which could significantly impact the pathophysiology and clinical evolution of the disease (Fig. 3). There is a crucial need for the restoration of proper Treg function in AR patients, which is regarded as one of the main therapeutic outcomes.

Fig. 3.

Dysregulation of Tregs in allergic diseases. The general number and the function of different subsets of Tregs are reduced in AR, allergic asthma, and food allergy. In AD, there are controversial data related to the number of Tregs, although their function is impaired. CCR5, C-C chemokine receptor 5; CRTH2, chemoattractant receptor-homologous molecule expressed on Th2 cells; FcεRI, IgE high affinity receptor; ILT3, immunoglobulin-like transcript 3; iTr35, IL-35-inducible Tregs; pDC, plasmacytoid dendritic cell; Teff, effector T; TFR, follicular Tregs; TGF-β, transforming growth factor β; Tr1, IL-10-producing Tregs; Treg, regulatory T cell; tTreg, thymus-derived Tregs.

Fig. 3.

Dysregulation of Tregs in allergic diseases. The general number and the function of different subsets of Tregs are reduced in AR, allergic asthma, and food allergy. In AD, there are controversial data related to the number of Tregs, although their function is impaired. CCR5, C-C chemokine receptor 5; CRTH2, chemoattractant receptor-homologous molecule expressed on Th2 cells; FcεRI, IgE high affinity receptor; ILT3, immunoglobulin-like transcript 3; iTr35, IL-35-inducible Tregs; pDC, plasmacytoid dendritic cell; Teff, effector T; TFR, follicular Tregs; TGF-β, transforming growth factor β; Tr1, IL-10-producing Tregs; Treg, regulatory T cell; tTreg, thymus-derived Tregs.

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Tregs in Allergic Asthma

Asthma is a heterogeneous chronic inflammatory disease of the airways affecting 1–29% of the population in different countries. Asthma is characterized by variable respiratory symptoms, such as wheeze, shortness of breath, chest tightness, and/or cough usually associated to reversible airflow obstruction, bronchial hyperresponsiveness, chronic inflammation, and remodeling [8, 108]. Asthma encompasses different phenotypes and endotypes with specific pathophysiological mechanisms [109]. It is broadly divided as type 2 and non-type 2 immune-mediated according to the expression levels of eosinophils in blood and sputum, the exhaled nitric oxide (FeNO), as well as total and specific IgE. Type 2 allergic eosinophilic asthma is characterized by blood eosinophilia, tissue eosinophilia, elevated FeNO, elevated serum IgE, and type 2 comorbidities such as AR, chronic rhinosinusitis with nasal polyps, eosinophilic gastrointestinal disorders, and AD [8, 110].

Tregs play an essential role in the pathogenesis of asthma. They inhibit the proximal pathways of allergic sensitization and IgE production in response to allergen exposure [13]. Alveolar macrophages and pDCs are the main cells promoting FOXP3+ Tregs in the lung [111, 112]. In severe asthma, it has been demonstrated that patients display lower numbers of FOXP3+ Tregs compared to healthy controls in the bronchoalveolar lavage fluid, and this is accompanied by reduced number of circulating Tregs [113, 114] and impaired chemotaxis of Tregs to lung epithelial cells [115]. CCR5 expression levels on FOXP3+ Tregs, associated with strong suppressive activity, were significantly decreased in severe asthma patients compared to the mild-to-moderate asthma and control groups, and the CCR5 protein expression levels on FOXP3+ Tregs positively correlated with lung function parameters in patients with severe asthma [113]. Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) is a type 2 receptor for prostaglandin D2 (PGD2) that is expressed on Th2 and other cell types such as Tregs [14]. It has been reported that the frequency of CRTH2+ Tregs was increased in patients with asthma, especially during an acute asthma exacerbation, correlating with asthma control [116]. Therefore, asthmatic patients display lower numbers of Tregs, with low CCR5 expression and high CRTH2 expression, demonstrating lower functionality and a Th2-biased character.

Severe exacerbations are an important cause of morbidity and mortality in asthma, and respiratory infections with rhinoviruses are highly associated with them [117]. It has been demonstrated that Tregs lose part of their suppressive capacity after rhinovirus infection, being less able to inhibit Th2-type cytokines [118]. Another known risk factor for asthma exacerbations is the exposure to high concentration of ambient air pollution [119]. The ambient air pollution exposure is one of the factors that can affect Tregs functionality in the lung. Exposure to particulate matter (PM) amplifies Th2/Th17 cell responses and reduces Tregs numbers [120], which is mediated by epigenetic changes. Exposure to PM induces hypermethylation of the CpG islands in the FOXP3 locus, impairing Treg function and worsening asthma severity scores [119, 121]. Moreover, the uptake of PM by alveolar macrophages activates the aryl hydrocarbon receptor (Ahr), resulting in the induction of Notch ligand Jagged 1 (Jag1), which interacts with iTregs to drive their destabilization [122, 123]. This Ahr-Jag1-Notch cascade promotes allergic airway inflammation [123]. Recent studies have identified Notch4 as the Notch receptor on Tregs involved in these interactions, which is upregulated in an IL-6-dependent manner in circulating Tregs of subjects with asthma according to disease severity [124, 125]. Interestingly, targeting IL-6 receptor pathway led to an increase in the immunosuppressive capacity of Tregs in association with suppression of Notch4 expression, which may provide benefit in patients with severe asthma [126‒128].

Omalizumab, a recombinant humanized mAb against IgE that has been used to treat severe allergic asthma in children and adults for many years [108], demonstrated to increase Treg frequency in asthmatic children, which correlated with asthma control [129]. Omalizumab restores in vitro the ability of pDCs from atopic donors to produce IFN-α and Tregs by blocking the signaling induced by the crosslinking of the IgE high affinity receptor (FcεRI) and IgE [130]. Interestingly, ligelizumab, a humanized anti-IgE mAb with higher affinity for IgE than omalizumab, demonstrated stronger capacity than omalizumab to block the binding of free IgE to FcεRI on pDCs, retaining also the capacity to restore the ability of pDCs to generate FOXP3+ Tregs [131].

Therefore, accumulated evidence points out the pivotal role of Tregs in allergic asthma (Fig. 3). The impaired function and decreased presence of Tregs in the lung can worsen asthma pathology, making Tregs promising candidates for the development of effective therapies.

Tregs in Food Allergy

The prevalence of food allergy has dramatically increased over the last decades, affecting up to 8% of children and 10% of adults, represents a worldwide health problem with a significant socioeconomic impact [132]. Several factors have been suggested as contributors to the development of food allergy or sensitization, including genetic predisposition, manifestation of atopic disease, family history of food allergy, increased hygiene, exposome, or the timing and route of exposure to foods [133]. Cow’s milk, egg, peanut, wheat, or tree nuts are among the most common food allergens in children, while frequent allergens in adults include peanuts, tree nuts, shellfish or fish. In addition, multiple food allergies are common [134‒136]. There is a clear association of food allergies with AD, AR, and asthma [137]. Oral tolerance is the appropriate immune response against food antigens encounter in the gastrointestinal tract in nonallergic individuals. However, a breakdown in this process leads to the development of food allergy. Allergen sensitization might occur not only in the gastrointestinal tract but also through the skin or the respiratory tract. The subsequent exposure to the food allergen triggers the degranulation of immune effector cells, resulting in the rapid manifestation of symptoms such as rash, hives, or gastrointestinal disorders. In more severe cases, patients may suffer respiratory or cardiovascular alterations and anaphylaxis [138, 139].

The key role of Tregs in the induction of oral tolerance has been long recognized. Food antigen-stimulated DCs generate Tregs by mechanisms depending on retinoic acid, IDO, or TGF-β. The expression of CCR9 and integrin α4β7 on the generated Tregs regulates their migration to the gut [140]. In addition, metabolites derived from gut microbiota contribute to the induction of tolerogenic pathways [136, 138, 140, 141]. As mentioned above, the pivotal role of Tregs in avoiding mast cell degranulation and type 2 cytokine production highlights their function in avoiding the development of allergic process. In fact, food allergy has been associated with a compromised generation and functionality of allergen-specific Tregs, which was demonstrated in a mouse model with enhanced IL-4 receptor signaling (Il4raF709) [142]. Supporting these findings, the transfer of Tregs prevents the anaphylaxis in a murine model of food allergy with ovalbumin [143]. Patients with food allergy have lower percentage of circulating Tregs than healthy controls [144‒146]. Moreover, the age-related increment of CCR6 expression on FOXP3+ Tregs from healthy controls was absent in food-allergic children. This lack of CCR6 could condition the migration of Tregs to peripheral sites of inflammation and, consequently, impairing tolerance induction [144]. Regarding other Treg subsets, peanut-specific CD49b+LAG-3+ Tr1 cells induced in vitro from peanut allergic patients have a defective functional capacity compared to those Tregs from healthy controls [147]. ROR-γt+ Tregs are involved in the maintenance of oral and intestinal homeostasis and preventing food adverse reactions by inhibiting type 2 responses [148]. Of note, in allergic patients, the frequency of circulating ROR-γt+ Tregs decreased [149]. Additionally, the frequency of tTregs at birth is also reduced, supporting the importance of tolerance development during the first year of life [150]. In infants, a significant frequency of allergies to cow’s milk, egg, wheat, or soy tends to outgrow during the following years [151]. It has been reported that a considerable increased of allergen-specific FOXP3+ Tregs are induced in children who develop tolerance to cow’s milk, eggs, or peanuts [146, 152, 153]. Although further studies are needed, a plethora of data indicate that Tregs play an important role in the natural resolution of food allergies and acquisition of tolerance.

In conclusion, food allergy is clearly associated with the deficient induction and function of Tregs, significantly contributing to the promotion of the allergic response (Fig. 3). Therapeutic strategies for food allergy should focus on restoring the immune tolerance with a significant emphasis on generating and enhancing Treg activity.

Tregs in AD

AD is a chronic inflammatory skin condition that affects approximately 2–3% of adults and 10–20% of children [154]. Characterized by intense itching, dry skin, and skin rashes, the etiology of AD involves a complex interplay between genetic, environmental, and immunological factors [155, 156] with a key role played by Th2 cell hyperactivation [157]. This dysregulated immune response leads to chronic inflammation and disruption of the skin barrier function, contributing to the development of AD symptoms. Emerging evidence suggests that Th22 and Th17 responses also play a role in AD development, with these CD4+ Th subsets infiltrating the lesional skin and peripheral blood of AD patients [158‒161].

CD25+FOXP3+ Tregs constitute 5–10% of T cells in the normal human skin [162]. These skin-resident Tregs exhibit a remarkable diversity of skin-homing molecules, including CCR2, CCR4, CCR6, and cutaneous lymphocyte-associated antigen (CLA), that enable their efficient recruitment to the skin [163, 164]. Intriguingly, skin Tregs also express GATA3 and RORα transcription factors that have been linked to their functional properties. Mice deficient in these transcription factors in Tregs exhibit spontaneous Th2-type skin inflammation, highlighting the importance of these molecules in Treg function [165, 166].

The ability of Tregs to regulate immune responses and their capacity to infiltrate the skin make them a potential player in the development of AD [167]. Studies of genetic disorders that affect Treg function have provided compelling evidence for their involvement in AD. Immunodeficiency, polyendocrinopathy, and enteropathy X-linked syndrome and Wiskott-Aldrich syndrome that generate dysfunctional Tregs due to FOXP3 gene mutations or defective Wiskott-Aldrich syndrome proteins, respectively, offer the strongest evidence of the implication of dysfunctional Tregs in AD pathogenesis, as these diseases exhibit skin eczematous manifestations that resemble AD lesions [51, 168]. Similarly, mice lacking Tregs (scurfy mice) develop eczematous dermatitis, mimicking the skin lesions observed in AD. Furthermore, several treatments developed for allergic disorders that either generates or modulates Treg function have demonstrated benefits for AD patients. A recent systematic review showed significant reductions in the severity of AD in children following treatment with allergen immunotherapy (AIT) and vitamin D supplements, both of which have the potential to increase Treg numbers or enhance their function [169, 170].

Despite the well-established presence of T cells in AD skin, the recruitment of Tregs and their potential dysfunction in AD remain enigmatic. Some studies have identified increased frequencies of CD25+FOXP3+ Tregs in the lesional skin and blood of AD patients [171‒174], whereas others have reported absence, lower frequency, or no significant variation [175‒178]. A recent meta-analysis, all including Chinese populations, showed that patients with AD had an increased proportion of Th22 cells, Th17 cells and a decreased proportion of Tregs in peripheral blood [179]. These discrepancies could be attributed to the heterogeneity of Tregs, different analyzed markers, disease status, treatments that affect Treg numbers such as glucocorticoids, UV radiation [180], ciclosporin [181], and the fact that FOXP3 is expressed transiently in T effector cells in the skin, making it difficult to accurately assess their true numbers. Furthermore, even when higher Treg numbers are observed, their function may be compromised. It has been reported that despite having an increased number of CD25highFOXP3+CCR4+CLA+ Tregs in AD compared to controls, there is a subpopulation with this regulatory phenotype that lacks expression of CCR6, with the ability to promote Th2 responses [171]. Similarly, another study reported that patients with moderate to severe AD had higher total Treg numbers than healthy controls; however, the ratio of specific Tregs to T effector cells was lower, resulting in higher levels of IL-4 and IL-13 [182]. Another study which identified higher frequencies of circulating Tregs in AD, also observed impaired generation of iTregs in AD associated with lower expression of the TGF-β surface anchor GARP (glycoprotein A repetitions predominant), which could explain a reduced capacity of Tregs in AD to control inflammation [183‒185]. In addition to potential quantitative and functional impairments, Tregs also exhibit high plasticity, being able to differentiate into Th1, Th17, or Th2 cells through epigenetic reprogramming under the influence of cytokine signaling [49, 186, 187], potentially overcoming their suppressive functions and contributing to AD exacerbation [188].

The role of Tregs in the pathogenesis of AD is complex and remains an area of active research (Fig. 3). Further studies are needed to fully understand how Treg dysfunction contributes to AD development and how to enhance Treg function as a therapeutic target for AD treatment.

AIT is currently the only treatment with potential long-lasting disease-modifying effects for allergic diseases. It consists in the administration of high doses of the causative allergens to induce sustained tolerance after treatment discontinuation, which can be defined as a long-term clinical tolerance upon natural exposure or in vivo challenges [11]. Up to date, AIT is indicated for patients with allergic rhinoconjunctivitis, hymenoptera sensitivity, allergic asthma (only for controlled patients), and some food allergies, especially peanut, cow’s milk, and hen’s egg allergy [12, 189]. Compelling evidence has demonstrated that subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), as well as oral immunotherapy for the management of food allergies show safety and efficacy for many allergic patients [190]. Other alternative routes of administration such as epicutaneous immunotherapy or direct injection into lymph nodes (intralymphatic immunotherapy), have been explored to attempt to improve safety and patients’ convenience while maintaining efficacy [191, 192].

The immunoregulatory mechanisms involved in the induction of allergen tolerance have been deeply studied both in patients receiving AIT and in healthy individuals who are naturally exposed to high doses of allergens, such as beekeepers or cat owners [13, 193]. The disease-modifying effects of AIT result from modulation of both innate and adaptive immune responses (Fig. 4) [10]. A very rapid desensitization of mast cells and basophils and apoptosis of allergen-specific Th2 cells occur together with an increase in Tregs and their cytokines [10, 194]. The capacity of Tregs to inhibit multiple cell types is essential to achieve cell-mediated tolerance. Tregs generated during AIT not only suppress effector cell functions but also induce the production of blocking antibodies [10]. As mentioned above, both tTregs and pTregs modulate allergen-specific Th2 cells by dampening responses via cell-cell interactions or by releasing anti-inflammatory mediators such as IL-10 and TGF-β, respectively [195]. IL-10 is crucial for effector T cell anergy and for allergen-specific IgG production [196]. The percentages of IL-10-producing CD49b+LAG-3+ Tr1 cells in allergic patients are significantly lower than in healthy subjects [97], which significantly increase after successful AIT [197]. It was suggested that the IL-10-related transcription factor E4BP4 plays a regulatory role, as its mRNA and the numbers of Tr1 cells were elevated in blood of patients treated with SCIT [198]. IL-35 has also been identified as an immunosuppressive cytokine produced by Tregs following AIT treatments, inhibiting cellular and humoral Th2 responses and IgE production in B cells [98].

Fig. 4.

Mechanisms of Treg-induced immune tolerance during AIT. Regulatory T cells (Tregs) are implicated in the suppression of effector cells (eosinophils, mast cells, and basophils), effector T cells (Th1, Th2, and Th17), inflammatory dendritic cells (DCs), type 2 innate lymphoid cells (ILC2s), NKT cells, and allergen-specific IgE production. In addition, Tregs promote the induction of tolerogenic DCs and the production of allergen-specific IgG4 and IgA antibodies.

Fig. 4.

Mechanisms of Treg-induced immune tolerance during AIT. Regulatory T cells (Tregs) are implicated in the suppression of effector cells (eosinophils, mast cells, and basophils), effector T cells (Th1, Th2, and Th17), inflammatory dendritic cells (DCs), type 2 innate lymphoid cells (ILC2s), NKT cells, and allergen-specific IgE production. In addition, Tregs promote the induction of tolerogenic DCs and the production of allergen-specific IgG4 and IgA antibodies.

Close modal

Special AT-rich sequence-binding protein 1 (SATB1) is crucial for Tregs phenotype and function. This genome organizer regulating chromatin structure and gene expression is generally repressed in functional Tregs [199]. Interestingly, SCIT and SLIT induced repression of SATB1 in FOXP3+ Tregs, which correlates with the clinical response [200]. A study on Der p 1-specific FOXP3+ Tregs after SCIT also demonstrated early increases in functionally efficient Tregs and downregulation of dysfunctional ILT3+ allergen-specific Tregs subset in allergic patients, associated with improved allergic symptoms after house dust mite immunotherapy [95].

Different studies support that the induction of long-term stable Tregs after AIT treatments is mediated by epigenetic rewiring [29, 201]. A HDM-SCIT study demonstrated a significant increase in the circulating percentages of TFR and restoration of their suppressive capacity, correlating with the clinical improvement [100]. Another study revealed an increase in TFR cells following SCIT and SLIT in grass pollen-allergic patients. ATAC-seq analyses showed differentially accessible chromatin regions in TFR cells between allergic patients and after SCIT and SLIT, suggesting that changes in the chromatin accessibility can contribute to tolerance induction following these treatments [202]. In addition, allergoid-mannan conjugates are next-generation AIT vaccines able to promote tolerogenic DCs with the capacity to induce highly suppressive FOP3+ Tregs by mechanisms depending on metabolic and epigenetic reprogramming [29, 30]. Phase II clinical trials demonstrated that allergoids-mannan conjugates show safety and efficacy in HDM and birch pollen allergic patients, and phase III clinical trials are currently ongoing [203, 204].

Successful AIT induces long-term immune tolerance toward allergens, reducing allergic symptoms, decreasing medication requirements, and improving the quality of life of patients. A key feature of AIT to achieve this tolerance is the generation of allergen-specific Tregs in allergic patients. The better understanding of the mechanisms implicated in the mode of action of AIT vaccines could help pave the way for the improvement of treatments and for the identification of novel biomarkers.

Our understanding on the immunological mechanisms underlying allergic diseases and their treatments has significantly improved over the last decades. Nowadays, it is widely accepted that the restoration and maintenance of allergen tolerance is a hallmark of sustained healthy immune responses to allergens. In this context, allergen-specific Tregs play a critical role both in the prevention of allergic diseases and in the induction of allergen tolerance during successful AIT and after treatment discontinuation. Aberrant Treg function is a common feature of crucial in the pathogenesis of different disorders characterized by a misbalance in the immune response to foreign and self-antigens such as allergic, autoimmune, and chronic inflammatory diseases. Up to date, AIT remains the only treatment with potential capacity to restore the course of the disease, and intensive research is being done to gain mechanistic insights into the complex mechanisms underlying its mode of action. The better understanding of the molecular mechanisms involved in the regulation of FOXP3 expression and stability in Tregs might well contribute to improve and develop novel Treg-based therapeutic strategies for allergic diseases.

Dr. Oscar Palomares received research grants from MINECO, Ministerio de Ciencia e Innovación, Inmunotek S.L., Novartis, and AstraZeneca, and fees for giving scientific lectures or participation in advisory boards from: AstraZeneca, Pfizer, GlaxoSmithKline, Inmunotek S.L., Novartis, and Sanofi-Genzyme. The rest of authors have no conflict of interest to declare.

This work was supported by grant PID2020-114396RB-I00 to O.P. from MICINN, Spain.

O.P. conceived and designed the review. A.A., C.B.-V., L.M.-C., S.S., and O.P. wrote the manuscript. All authors approved the final version of the manuscript.

Additional Information

Edited by: H.-U. Simon, Bern.Leticia Martín-Cruz and Cristina Benito-Villalvilla contributed equally to this work. Alba Angelina and Oscar Palomares share last authorship and corresponding authorship.

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