γδT17/γδTreg cell subsets: a new paradigm for asthma treatment

Abstract

Bronchial asthma (abbreviated as asthma), is a heterogeneous disease characterized by chronic airway inflammation and airway hyperresponsiveness. The main characteristics of asthma include variable reversible airflow limitation and airway remodeling. The pathogenesis of asthma is still unclear. Th1/Th2 imbalance, Th1 deficiency and Th2 hyperfunction are classic pathophysiological mechanisms of asthma. Some studies have shown that the imbalance of the Th1/Th2 cellular immune model and Th17/Treg imbalance play a key role in the occurrence and development of asthma; however, these imbalances do not fully explain the disease. In recent years, studies have shown that γδT and γδT17 cells are involved in the pathogenesis of asthma. γδTreg has a potential immunosuppressive function, but its regulatory mechanisms have not been fully elucidated. In this paper, we reviewed the role of γδT17/γδTreg cells in bronchial asthma, including the mechanisms of their development and activation. Here we propose that γδT17/Treg cell subsets contribute to the occurrence and development of asthma, constituting a novel potential target for asthma treatment.

Keywords:

• Asthma
• γδT17/γδTreg
• mechanism

Introduction

As a subgroup of T cells, γδT cells are immune cells composed of T cell antigen receptor (TCR)-γ and TCR-δ (1) that plays an important role in innate and specific immunity. There is evidence that Vγ1⁺ γδT cells can induce eosinophilic inflammation (2), while Th2 and eosinophilic T cells can induce airway inflammation and airway hyper reactivity (AHR) by secreting a large number of inflammatory cytokines (3). As an important source of IL-17 production, γδT cells can recruit concentrated granulocytes and participate in a variety of inflammatory diseases (4,5). Indeed, IL-17 is associated with airway inflammation, hyper reactivity and remodeling in asthma (6–10). The production of IL-17 by γδT cells is performed by γδT17 cells (11) and compared with other T lymphocytes, the expression of IL-17 in γδT cells is reportedly higher (12). Studies have shown that γδT17 is involved in the pathogenesis of asthma (13) and that upon the inhibition of IL-23R, the inactivated Mycoplasma sputum attenuated the immune response mediated by γδT17 cells, and alleviated the airway inflammation and AHR in asthmatic mice (3). Regulatory γδT cells (γδTregs) are a newly reported subset of γδ T cells, which are characterized by the potential immunosuppressive function of TCRγδ and Foxp3 (14).

Γδt cell

Composition, structure and activation pathway of γδT cells

According to the TCR receptor, T cells can be divided into α-β T and γ-δT cells. The arrangement of γδT cells is composed of TCR-γ and TCR-δ. Major histocompatibility complexes do not restrict TCRγδ, thus their antigen recognition is independent of CD4 or CD8 co-receptors. Unlike αβT cells, γδT cells constitute only a small proportion (1–5%) of the lymphocytes that circulate in the blood and peripheral organs of most adult animals. γδT cells are, however, more widespread within epithelial-rich tissues, such as the skin, intestine and reproductive tract, where they can comprise up to 50% of T cells (15). The percentage of γδT cells in lymphoid tissue, intestinal tract and skin-related lymphoid system is similar.

Human γδT cells can be divided into Vδ1 and Vδ2 according to the Vδ chain. Vδ1⁺ T cells are mainly distributed in the epithelium and mucosa and Vδ2⁺ T cells, which usually express V19, are mainly in the peripheral blood and lymphatic system. Mouse γδT cells can be divided into two groups according to the Vδ chain: Vγ2, Vγ3, Vγ5, Vγ6 and Vγ7 being mainly expressed in peripheral lymphoid organs, while Vγ1 and Vγ4 are preferentially expressed in the respiratory system. In recent years, mouse and human γδT cells were shown to play an important role in maintaining the immune homeostasis of the local microenvironment and in autoimmunity, cancer and other related diseases (16). The production of IL-17 (γδT17) by γδT cells is not induced by antigen, while IFN-γ (γδT1) can be induced by antigen. By activating TLR, γδT cells activate IL-17, which is involved in the expression of cytokines, chemokines and pattern recognition receptors, such as IL-1, IL-6, IL-18, IL-23 and TGF. TGF-β1 activates toll-like receptor 2 and the aromatic hydrocarbon receptor (17). It has been found that IL-1β and IL-23 can stimulate the production of IL-17 by γδT cells (18) and the release of IL-1β and IL-18 via the inflammasome-triggered pathway is an important source of IL-17 secretion by γδT cells (19).

Γδt cells and asthma

In ovalbumin (OVA)-induced asthmatic mice, the expression of OVA-specific IgE and igGl decreased in mice lacking γδT cells compared with those of wild-type mice (20). Meanwhile, IL-5, eosinophils and T lymphocytes were also decreased in the lungs of mice lacking γδT cells (20). Therefore, γδT cells can promote allergic airway diseases mediated by Th2 cells and secrete OVA-specific IgE by B cells. However, some studies have found that the level of OVA-specific IgE in serum of mice with OVA-induced asthma was increased after treatment with anti-γδTCR (21). These data show that γδT cells can regulate humoral immunity and exert a double regulatory effect. Indeed, it was found that Vγ1⁺ γδT cells could increase OVA-specific IgE, but vγ4⁺ γδT cells had the opposite effect (22).

In OVA-sensitized and -challenged asthmatic mice, Vγ1⁺ γδT cells increase AHR by inhibiting the production of IL-10 by CD4⁺ CD25⁺ T cells (23). Many studies have confirmed that γδT cells can inhibit AHR. In OVA-sensitized mice, the number of Vγ4⁺ γδT cells in the lung increased after airway stimulation, while the airway responsiveness increased after injection of Vγ4⁺ γδT cells. Adoptive transfer of Vγ4⁺ γδT cells into mice can therefore inhibit AHR (24). Nevertheless, the effect of γδT cells on AHR is complex and depends on the dominance of specific subpopulations. After treatment with an anti-γδTCR antibody, the staining of collagen around the airway was increased. The quantitative analysis of collagen around the bronchus showed an increased deposition of collagen fibers and TGF-β (25). Of note, TGF-β can promote pulmonary fibrosis and lead to airway remodeling, thus the absence of γδT cells further aggravates airway remodeling. It was shown that γδT cells could inhibit AHR and inflammation in asthmatic mice; however, whether this is related to its subgroup still needs further clarification.

The function of γδT cells in clinical asthma is still controversial. Clinical studies have found that the human IL-4 production phenotype Vγ1⁺ Vδ1 subgroup can increase allergic inflammation, while the IFN-γ production phenotype Vγ2⁺ Vδ2 subgroup can regulate allergen-specific immune shift to Th2 (26). A previous study has found an increasing trend in the proportion of γδT cells in patients with asthma compared with that of healthy people (27), however another study observed that the proportion of γδT cells in patients with asthma was similar to that of healthy people (28). We speculate that in the process of asthma the number and function of γδT cells as well as the proportion of γδT cell subsets is changed. The underlying mechanism of the effect of γδT cells on asthma is still unclear. Further investigation of the mechanism pertaining the occurrence and development of allergic diseases can provide novel targets for the treatment of asthma in the future.

Γδt17/γδTreg cell

Γδt17 cell

IL-17 was originally thought to be produced by α- and β-T lymphocytes, but further studies have found that several immune cells secrete this cytokine, including γδT cells, cytotoxic T cells, naive natural killer T (NKT) cells, innate lymphoid CEUS (ILC) and lymphoid tissue-inducing cells (29). IL-17 and its closely related cytokine IL-17F can activate the mitogen-activated kinase (MAPK) pathway, classic NF-KB and C/EBPβ pathways through IL-17RA/RC. In various models of infection, cancer and autoimmune diseases, γδT cells were shown to be the main source of pro-inflammatory cytokines IL-17 and INF-γ.

γδT lymphocytes are produced by common progenitor cells in the thymus and are directly involved in the occurrence and development of asthma. The majority of αβ CD4⁺ T cells leave the thymus as "immature" cells. These cells differentiate after the activation of peripheral cells, while γδT cells play a role in the development of the thymus (30). Therefore, mouse γδ thymocytes contain subsets that are fully committed to IFN-γ or IL-17 production. These subsets can be distinguished according to the expression of co-stimulatory receptors CD27 and chemokine receptor CCR6 (31–33). Studies have shown that the potential mechanisms of the fate difference of γδ thymocytes include the controversial role of signaling through TCR (30). The variable region of the gamma chain (Vγ) (15) is also related to the bias of effectors (34). In particular, the production of IL-17 is mainly limited by Vγ4⁺ or Vγ6⁺ γδT cell subsets, although there are some exceptions with regards to Vγ1⁺ γδT cells (35,36). In fact, high-resolution transcriptome analysis of γδ thymocyte subsets showed that Vγ4⁺ and Vγ6⁺ γδT cells clustered together and were isolated from Vγ5⁺, Vγ1⁺ and Vγ7⁺ subsets (37). The main differences between these cells are two high-mobility family box transcription factors Sox4 and Sox13, which are essential for the development of Vγ4⁺ and Vγ6⁺ γδT17 thymocytes (38). However, mature peripheral blood Vγ6⁺ γδT17 cells bypass the need for Sox4 and Sox13, while there are no Vγ4⁺ γδT17 cells in Sox4^-/- and Sox13^-/- mice (38).

Regarding the mechanism, Sox13 induces the expression of BLK, which is a crucial signal transducer for the development of γδT17 cells (37). Together with Sox4, it controls the expression of RORγt20, which is the main "Type 17" transcription factor of γδT and similar cells (39–41). Interestingly, the locus encoding RORγt is controlled by epigenetic mechanisms in γδT cells, which accumulates positive modifications of histone H3 related to gene transcription in CD27-CCR6⁺ subpopulations that produce γδT17 cells. Therefore, there is a complex regulatory mechanism of differentiation and transcription in γδT17 cells (30,40,42). For "pre-programmed" mouse γδT cells, their peripheral activation is usually faster and simpler than other lymphocytic cells carrying rearranged antigen receptors. In fact, even in the absence of TCR stimulation, IL-1β and IL-23 stimulation were sufficient to trigger IL-17 secretion by CD27-CCR6⁺ γδT cells in vitro, however stimulations with TGF-β or IL-6 alone led to no effect (17,32,41,43). The innate pattern activated by mouse γδT17 cells is highlighted by its rapid response to pathogen-related molecules such as lipopolysaccharide or lipoproteins (ligands of receptor TLR4 and TLR2, respectively). Such rapid response is mediated by IL-1β and IL-23 derived from bone marrow cells, such as macrophages (43–45). In addition, IL-1β and IL-23 could also induce the production of IFN-γ by γδT17 cells (40,41). This peripheral plasticity of γδT17 cells is shown by the permissive chromatin configuration of the IFN-γ locus in CD27-CCR6⁺ γδT cells (40), which occurs when considerable inflammation occurs in the body (46–48).

For T cell subsets, the TCR reactivity of γδT17 cells remains controversial. TCR and CD3 agonists do not phosphorylate TCR-dependent kinases (such as ERK) nor do they induce rapid mobilization of calcium, in spite of causing extensive cell death (44,49). In an in vivo model with clear TCR specificity, a discrete population of γδT cells (approximately 0.4%) could recognize phyco-erythrodin and differentiate into IL-17 producing cells (50). T cells expressing the γδT cell receptor (TCR) are an important innate source of the proinflammatory cytokines interleukin-17(IL-17A) and IL-17F (51–53). Compared with CD4+ Th17 cells, γδT17 cells cells can respond to various stimuli immediately, including IL-23, IL-1 and their TCR triggering (32,52,54,55). Study shows that γδT17 cells are involved in the defense against mucocutaneous infections, and other microbial infections (31,56–59). IL-17 production by γδT cells has been shown to play important rolesanticancer in immune responses, in the pathology of autoimmune encephalomyelitis, and in the inflammatory processes associated with brain injury (60–64). Furthermore, the IL-17A and IL-17F absence or mutations in their signaling pathway lead to chronic mucocutaneous candidiasis, and they are particularly important for control of mucocutaneous infections in humans (65,66). There is some evidence that two distinct TCR-defined IL-17-producing γδT cell subsets also exist in humans, but unlike the mouse γδT-17 cells, these cells are probably not imprinted with an IL-17 bias during thymic development, but rather acquire an IL-17 bias in the periphery (67). Although it was shown that there is little study about the production of γδT cells on human IL-17 (68,69), but studies found that Human γδT17 cells appear to be crucial for immune responses in young individuals (70–73). TCR engagement favors the development of γδT cells precommitted to make interferon-g(IFN-g) (33), but, it is unclear whether development of γδT17 cells is at all dependent on positive selection via TCR signaling. There are reports that development of γδT17 cells occurs either TCR independently (33,74), or requires a weak TCR signal (75). Study shows that γδT17 cells appear in the embryonic thymus, and their number progressively decreases in adult mice with age (31,76). γδT17 cells comprise semi-invariant Vγ6+ γδT cells as well as more polyclonal Vγ1+ and Vγ4+ cells in lung, peritoneal cavity, and secondary lymphoid organs (35,58,77). It has been showed that the receptor proximal tyrosine kinase Syk is essential for γδTCR signal transduction and development of γδT17 in the mouse thymus, Syk induced the activation of the PI3K/Akt pathway upon γδTCR stimulation, mice deficient in PI3K signaling exhibited a complete loss of γδT17, without impaired development of IFN-γ-producing γδT cells; Moreover, γδT17-dependent skin inflammation was ameliorated in mice deficient in RhoH (78). Study demonstrate that IL-1β and IL-23 together are able to promote the development of bona fide γδT17 cells from peripheral CD122-IL-23R- γδ T cells, whereas CD122+ γδ T cells fail to convert into γδT17 cells and remain stable IFN-γ producers (γδT1 cells), IL-23 is instrumental in expanding extrathymically generated γδT17 cells,In particular, TCR-Vγ4+ chain-expressing CD122-IL-23R- γδT cells are induced to express IL-23R and IL-17 outside the thymus during skin inflammation; In contrast, TCR-Vγ1+ γδ T cells largely resist this process because prior TCR engagement in the thymus has initiated their commitment to the γδT1 lineage (18). It has found that TCR δ-deficient mice had a more severe dextran sodium sulfate (DSS)-induced colitis that was reduced upon reconstitution of γδT17 cells but not IFNγ-producing γδT cells (3). For γδT17 cells, TCR ligand interaction has a low affinity, while a strong TCR signal can easily trigger activation-induced cell death. Under the condition of homologous interaction with proteins, in addition to experiencing proliferation and developing a CD44hiCD62Llo phenotype, the expression of IL-23R and IL-1R1 is up-regulated in γδT17 cells. Studies have shown that CD28, BTLA and PD-1 are important regulators of the γδT17 cell subsets. The data showed that the number of γδT17 cells in mice infected with CD28 deficiency of Plasmodium falciparum increased, while BTLA and PD-1 produced IL-17 by negatively regulating skin cd27- γδT cells, which affected psoriasis-like skin inflammation (79,80). Thus, the activation of γδT17 cells relies mainly on innate cytokines but is regulated and fine-tuned by various accessory receptors.

Γδtreg cells

Treg are a kind of T cell subsets that control autoimmunity in vivo. Regulatory T cells can be divided into natural regulatory T cells (nTreg) and induced adaptive regulatory T cells (aTreg or iTreg), such as Th3 and Tr1. In addition, CD8 Treg and NKT cells are closely related to the occurrence of autoimmune diseases since their abnormal expression can lead to autoimmune diseases. Tr1 cells secrete IL-10 and Th3 cells secrete TGF-β, while in 1995, Sakaguchi found that nearly 10% of the peripheral CD4⁺ T cells in adult mice expressed the IL-2 receptor α chain CD25. Removal of these cells leads to a variety of autoimmune diseases in mice, and reinfusion of these cells can prevent the occurrence of such diseases. In addition, Treg cell activity is affected by many cytokine interactions in the thymus, which is essential for maintaining self-tolerance (81). Therefore we herein refer to these cells as CD4⁺ CD25⁺ Treg

Studies have shown that Treg cells play a key role in the occurrence and development of immune diseases. Treg cells can inhibit the proliferation of T cells and the production of cytokines, and play an important role in the prevention of autoimmunity. In the presence of IL-10 and TGF-β, repeated stimulation of TCR can induce Treg production. IL-2 is also essential for Treg cell homeostasis, function and development since in the absence of IL-2, Treg cells are unable to proliferate and survive (82–84).

There are similarities and differences between iTreg and nTreg cells. iTreg is similar to nTreg in phenotype and function, but there are differences in their epigenetic state and stability (85). It is known that Treg can inhibit effector T lymphocytes by three mechanisms. First, through direct contact inhibition, Treg cells can produce IL-10, IL-35, TGF-β, galetin-1 and other inhibitory cytokines, as well as cytotoxic factors and perforin release (86). Second, through the release of granular enzymes, such as a serine protease family called granzyme. Finally, through the interference of the metabolism of target cells mainly through IL-2, CD39 and CD73 pathways (87).

Treg cells play an important role in inhibiting infection, maintaining autoimmune tolerance and tumor induced-immune responses. Forkhead box protein-3 (Foxp3) is a transcription factor for Treg cell differentiation. TGF-β is also involved in Treg cell differentiation. Treg cells play a protective role in the tissue damage of infectious diseases by producing immune tolerance to autoantigen and inhibiting autoimmune reaction. From mature T cells in the thymus to peripheral tissues, natural Treg cells inhibit the activated T cells, while adaptive Treg cells inhibit initial T cells in peripheral lymphoid tissues after antigen activation.

It was reported that TGF-β1 and IL-15 can induce Foxp3⁺ γδTreg cells, thus inhibiting the proliferation of PBMC-stimulated cells by anti-CD3 and anti-CD28 antibodies (88). Indeed, anti-human TCRVδ1 antibody and TGF-β1 in vitro expanded Vδ1 T cells that mainly expressed Foxp3, CD25, glucocorticoid-induced TNFR family-related proteins and CTLA4, all of which inhibit the proliferation of CD4⁺ T cells (89). IP-10 secreted by breast cancer cells can induce the infiltration of γδTreg cells, thereby inhibiting T cell response and DC maturation (90). These regulated γδT cells lack the expression of Foxp3, girt and CD25, and their inhibitory activity does not produce TGF-β1 or IL-10. These studies identified a new subtype of γδTreg, whose CD39 expression accounted for 60% of γδT17 cells and were polarized by TGF-β1. Therefore, this subset has a stronger immunosuppressive effect than that of CD4+ Treg cells in colorectal cancer. These CD39+ γδTreg cells inhibited the activity of human CD3+ T cells in an adenosine-dependent manner (91).

In the presence of TGF-β1 and IL-2, γδTreg cells can be produced by anti TCRγδ stimulation in vitro. Similar to CD4⁺ Foxp3⁺ Tregs, γδTregs also express Foxp3. In addition, Foxp3⁺ γδT cells mainly belong to the Vδ1 subset with a CD25 ⁺ CD27 ⁺ CD45RA2 phenotype. These cells show effective immunosuppressive function at least in vitro through an intercellular contact mechanism (92). As a recently reported subset of γδT cells, γδTreg cells are characterized by simultaneous expression of TCRγ δ and Foxp3 and have a potential immunosuppressive function. A previous report shows that Foxp3⁺ γδTregs are involved in some diseases, which may inhibit the activation and function of T cells involved in antigen-specific immune responses (93). Moreover, Treg cells can be recruited into the tumor microenvironment through immunosuppressive and metabolic factors (94).

The immunosuppressive activity of Tregs is one of the mechanisms that promote carcinogenesis (95). The frequency of Foxp3⁺ Tregs and CD8⁺ T cells and the density ratio of A2AR⁺/CD8⁺T cells, CD39⁺/Foxp3⁺Treg and CD73+/Foxp3 + Treg were detected by a multiplex immunofluorescence method. Tregs in gastric cancer metabolizes ATP into adenosine through A2AR pathway, while it induces apoptosis, inhibits the proliferation of CD8⁺ T cells, and leads to the immune escape of gastric cancer (96). Data indicate that the IL6-adenosine loop between CD73⁺γδTregs and CAFs is important to promote immunosuppression and tumor progression in human breast cancer, which may be critical for tumor immunotherapy (97). Consequently, modulating CD73 or cancer-derived adenosine in the tumor microenvironment emerges as an attractive novel therapeutic strategy to limit tumor progression, improve antitumor immune responses, avoid therapy-induced immune deviation, and potentially limit normal tissue toxicity (98). In addition, it was the first description that IL-23R-expressing γδT cells can inhibit regulatory T cells from two pathways after being activated by IL-23. First by inhibiting the differentiation of Treg and second through directly inhibiting the function of Treg (63). However, the full mechanism of IL-23-activated γδ T cells inhibiting regulatory T cells is still unclear. The discovery of specific active molecules that inhibit Treg can lead to novel clinical therapeutic targets. It may also be a new therapeutic strategy to use Treg-mediated immune regulation and immunosuppression mechanisms in the treatment of asthma.

Regulatory cells include regulatory T cells (Tregs) and regulatory B cells (Bregs), which play important roles in immune modulation (99–101). There are importances of Bregs in the pathobiology of different diseases, including graft rejection and tolerance mechanisms (102). Flores-Borja, F. et al. proposed a dual capacity of CD19 + CD24hiCD38hi Bregs in maintaining the pool of Tregs and Th1/Th17 populations through controlling over-production of proinflammatory cytokines, preventing engagement of CD4 with Th1 and Th17 and participating in converting effector T cells into Tregs (103). Studies have shown that, healthy CD19(+)CD24(hi)CD38(hi) B cells inhibited naïve T cell differentiation into T helper 1 (T(H)1) and T(H)17 cells and converted CD4(+)CD25(-) T cells into regulatory T cells (T(regs)), in part through the production of IL-10. However,in patients with Active rheumatoid arthritis, CD19(+)CD24(hi)CD38(hi) B cells with regulatory function may fail to prevent the development of autoreactive responses and inflammation, leading to autoimmunity (103). Tregs, Th17 cells and their balance are considered central for the homeostasis of immune responses and tolerance (104,105).An imbalance of these cells is closely linked to the pathogenesis of various diseases and conditions, including autoimmunity, transplant rejection and carcinogenesis (106,107). A correlation between decreased Tregs and the incidence of bronchiolitis obliterans syndrome (BOS) has been reported in lung transplantation recipients (108). In addition to Tregs being decreased or suppressed post transplantation, such as acute rejection may suppress the regulatory activity of Tregs. Patients in the acute rejection showed a predominance of Th17 cells, both in BAL and peripheral blood, and simultaneous impairment of Tregs resulting in a depressed Treg/Th17 ratio (109). The role of Tregs and Th17 cells in lung rejection has been widely investigated and the networks involving them have been proposed in a new immunological approach to transplantation (110,111).

Role of γδT17/γδTreg cells in asthma

Previous studies show that the key pathogenic basis of asthma is the imbalance between different T cell populations, especially that of the Th1/Th2 and Th17/Treg cells (112,113). However, these imbalances cannot fully explain the phenomena of asthma. In parallel, it was shown that γδT cells play a key role in the pathogenesis of asthma (92,114). The airway inflammation and AHR induced by γδ T cells are due to the secretion of a large number of inflammatory cytokines that stimulate Th2 type cells to produce eosinophilic inflammation (3). As an important source of IL-17 production, γδT can recruit concentrated granulocytes and participate in the occurrence and development of a variety of inflammatory diseases (4,5). IL-17 is associated with airway inflammation, AHR and airway remodeling in asthma (6–10). It was found that there was a high concentration of IL-17 in the blood and BALF of asthmatic patients, and it was confirmed that the concentration of IL-17 was positively correlated with the severity of asthma (115). Another study has shown that IL-17 may be a target factor for gene-targeted therapy of hormone-resistant asthma (116). γδT cell subsets were shown to drive the pathogenesis of asthma by increasing the production and release of inflammatory cytokines, and eventually lead to airway remodeling (114,117). High levels of IL-17 are associated with airway inflammation, responsiveness and remodeling in asthma (6,9,10).

There is evidence that Treg cells can improve airway remodeling and restore Th1/Th2 balance through the Dll4/Notch signaling pathway (118). TLR3 is highly expressed in mesenchymal stem cells and can increase Treg production through the Notch pathway after activation (119), while Treg cells can produce IL-10, inhibit Th2 type immune response factors such as IL-4, IL-5, IL-13, and prevent Th cells from secreting IL-17 (120). TLR3 can induce the differentiation of IL-17-producing T cells under the activation of the TLR3 ligand (121). TLR3 can also inhibit food allergy in mice by inducing IFN-γ Foxp3 Treg cells (122). IFN-γ Foxp3 Treg cells also play an important role in the occurrence and development of asthma, and TLR3 is also significantly expressed in the lungs. TLR3 may also regulate asthma through this mechanism, which needs further experiments to confirm.

Therefore, the pathogenesis of asthma is very complex, mainly involving the imbalance of Th1/Th2 of γδT cells (25). In addition, in allergic and autoimmune diseases, the Treg subsets of γδT cells are also dysregulated (23). There is also the involvement of γδT17/γδTreg cells in the occurrence and development of asthma (123), as shown in OVA-induced asthmatic mice (13). Therefore, γδTregs are a newly identified immunosuppressive γδT cell subgroup, which is characterized by the expression of TCR and Foxp3 (124).

Regulatory role of γδT cells in the treatment of asthma

This review attempts to comprehensively cover the influence of γδT cells on the occurrence and development of asthma. Therefore, it is important to use this new understanding to develop new methods for the diagnosis and treatment of asthma. Although γδT17/γδTreg cells are a subset of T cells, they play a key role in the process of asthma, as discussed above. In order to utilize the intrinsic activity of γδT17/γδTreg cells for asthma immunotherapy, it is essential to better characterize the human γδ T cell subsets and the mechanisms involved in various types of asthma. It is also necessary to understand the differentiation stage, activation status and central paradigm of immune checkpoint receptor expression of γδT cells, so that these can be activated persistently with effective anti-asthma medications. In asthma, γδT cells proliferate and activate, and the proportion of γδT cells change, showing a dominant response of γδT17. Through the activated γδT cells, the airway inflammatory response is regulated, and the specific mechanism needs to be studied.

Important questions should be addressed. First, whether the inhibition of γδT17 cells is beneficial to asthma patients. Second, if γδTreg can inhibit the Notch signaling pathway, regulate Th1/Th2 differentiation in asthma. Third, if it is possible to increase the immunosuppressive function of Tregs by inhibiting active molecules of γδT cells expressing IL-23R. Finally, if TLR3 can activate the immune response of Tregs through the overexpression of IFN-γ Foxp3 Treg cells.

Altogether, we are now in a favorable position to study asthma from the perspective of developmental biology and immune mechanisms, which will continue to provide valuable insights into the underlying role of γδT cells. The role of γδT cells in asthma is therefore a novel field of research. Since γδT cells are heterogeneous, it is necessary to thoroughly study the pro- and anti-asthmatic properties of different subpopulations of γδT cells, and use these to maximize the efficacy of immunotherapy.

Declaration of interest

The authors declare no conflict of interest.

Additional information

Funding

This work was funded by Mechanism of aerosol inhalation of inactivated Mycobacterium on reducing airway hyperresponsiveness in asthmatic mice by regulating γδ T cells (81470230).