Asthma is a chronic respiratory disease affecting the life of millions of people worldwide. The signs and symptoms are wheezing, cough and dyspnea. These asthmatic manifestations have a great impact on people´s life quality, especially in patients with uncontrolled asthma in low-income countries.

The pathogenesis of asthma is not completely understood as it has both genetic and environmental factors influencing the disease. Environmental triggers causing asthma development and exacerbation are allergens, air pollution, like cigarette smoke, as well as volatile organic compounds, household compounds or viral, microbial and fungal infections.

Atopy, a condition in which the immune system is more sensitive to common, otherwise not toxic substances, called allergens, is a triad of hyperreactive tissues (allergic eczema, in the skin, allergic rhinitis, in the nose and allergic asthma, in the lower airways). Allergen exposure still remains the strongest risk factor for developing allergic asthma in susceptible subjects. Therefore, the main focus of asthma research groups during the last decades has been the type 2 inflammatory responses, where T lymphocytes play a prominent role in the pathogenesis, in particular T-helper cells type 2 (TH2), their transcription factors and cytokines, e.g., Interleukin-4 (IL-4), IL-5 and IL-13 (1–5). Asthma is characterized by an imbalance between TH1 and TH2 response in the airways, following an overshooting response to a harmless antigen like allergens or pathogens. The hypersecreted cytokines IL-4, IL-5 and IL-13 lead to smooth muscle spasms, goblet cell hyperplasia and eosinophilic inflammation (6). As a result, new biological therapies such as monoclonal antibodies targeting IL-5 or IL-5 receptor were approved. Nevertheless, approximately half of asthmatics lack the type 2 phenotype, suggesting that asthma is a much more complex syndrome with many possible phenotypes. More recently, it became clear that type 2 innate lymphoid cells (ILC2) also play an important role and are main producers of IL-5 upon IL-33, IL-25 and TSLP stimulation. Additionally, T-helper cells type 17 (TH17) recruit neutrophils via IL-8 into the lung after antigen presentation. These neutrophils upregulate α-defensines and serine proteases thus characterizing a different manifestation of asthma than eosinophilic driven inflammation (7).

Most approaches to distinguish different asthmatic phenotypes are based on the origin and time point of the disease onset, as well as the symptom and treatment status of the patient. Siroux et al. described asthma phenotypes A-D. Group A was actively treated allergic childhood-onset asthma while B was actively treated adult-onset. Groups C (allergic) and D (non-allergic) were characterized by very mild symptoms and no need for treatment (8). Another approach was to do a cluster analysis using symptoms and eosinophilic inflammation as key parameters. Similarly, a common phenotype of early-onset atopic asthma was identified. In contrast to this type, there is a predominant eosinophilic inflammation phenotype with late onset of the disease. On the other hand the authors describe two symptom driven phenotypes, the early symptom predominant and the obese non-eosinophilic type (9). Especially patients with higher body mass index (BMI) and more eosinophilic inflammation were at risk risk of suffering more frequently from asthma exacerbations (10).

As respiratory virus infections are seen as one of many triggers for non-allergic asthma, the defense against those pathogens impacts asthma development as well. Depending on the different serotypes, rhinovirus shows a cytopathic effect on the bronchial epithelial cells. This cytotoxic effect could play an important role in increasing the susceptibility to asthma development (11). A large cohort study found an interaction between single nucleotide polymorphisms (SNPs) in the 17q21 locus, rhinovirus induced wheezing illness in childhood and asthma development (12). Despite these findings, it is still controversial whether RV infections are the cause or also a result of susceptibility to allergens and pathogens of asthmatic subjects.

Nevertheless, many asthmatics suffer from virus induced worsening of their disease, so called asthma exacerbations. These exacerbations can occur frequently and are defined as acute or subacute episodes of progressive worsening of symptoms as well as lung function. Mostly, upper and lower respiratory tract infections are responsible for these exacerbations. Characteristically, rhinovirus (RV) is considered to be the main trigger of asthmatic exacerbations, being detected in up to 70-80% of children and adult exacerbations (13–16).

Thus, it is crucial for asthmatic patients that their body produces antiviral proteins commonly known as interferons. These agents consist of three subfamilies called interferons type I, II and III. In this review, we focus on the type III interferon family also known as interferon-lambda 1-4. So far, the differential role of IFNs is not well understood although understanding their regulation might be an important target for therapeutic antiviral strategies. The current SARS-CoV-2 pandemic demonstrates even more how dangerous new virus mutations are and how essential a sufficiently controlled antiviral immune response is (17).

Here we will further discuss the role of RV infections as common triggers of asthmatic exacerbations and how type III IFNs affect them (18). Furthermore, in this narrative review, we will emphasize on the regulation and variability in the expression of interferon-lambda family members and the signaling via its receptor interferon-lambda receptor (IFNλR) (19).

The human rhinovirus (HRV) is a positive-sense single-stranded RNA [(+)ssRNA] virus belonging to the genus enterovirus of the picornaviridae family. Rhinoviruses are commonly known as respiratory viruses associated with infections of the upper respiratory tract and represent the main agent causing the common cold (20). Studies in recent years have additionally shown that HRV can trigger or promote lower respiratory tract diseases such as asthma exacerbations or other inflammatory lung diseases (21, 22).

Three species of HRV have been reported: RV group A (RV-A), RV group B (RV-B) and the recently discovered RV group C (RV-C). Together they comprise more than 100 serotypes that can be characterized by their receptor binding site (23). The majority of RV-A and RV-B, approximately 90% (major receptor group), enters the cell via binding intercellular adhesion molecule 1 (ICAM-1) (24). Attachment to ICAM-1 receptor leads to conformational change of the virus capsid and uncoating so that the viral genome can be released into the cytosol. The minority of HRV (minor receptor group) utilizes the low-density lipoprotein receptor (LDLR) for entering the host cell. Virus-attachment to the LDLR results in clathrin-dependent endocytosis and RNA-release into the endosome. After internalization of the receptor ligand complex by clathrin-mediated endocytosis, the internal ribosomal entry site (IRES) recruits the host translation machinery, including ribosomes, to initiate viral replication and protein biosynthesis ( Figure 1A ). In contrast, Cadherin related family member 3 (CDHR3) was recently described as a possible receptor for RV group C but little is known and this group needs further investigations (24).

Endosomal viral ssRNA can be recognized by the host via toll-like receptor (TLR) 7 and 8. During the viral replication process, double-stranded RNA (dsRNA) is produced. Viral dsRNA in the endosome can be detected by the host via the pattern recognition receptor (PRR) toll-like receptor 3 (TLR3) (25, 26). Cytosolic viral RNA can be recognized by retinoic acid-inducible gene 1 (RIG-1) or melanoma differentiation-associated gene 5 (MDA-5). Host detection of viral RNA by these PRR and pattern recognition molecules (PRM) consequently induces downstream signaling cascades. MDA5 interacts with the mitochondrial antiviral signaling proteins (MAVS) leading to recruitment of interferon regulatory factors (IRFs) 3 and 7 into the nucleus, binding to the promotor of INFλ and resulting in induction of the IFNλ family gene expression (27–29). This signaling pathway not only induces type III interferon production but also leads to higher expression of type I interferons (30). Downstream of TLR 7/8 and TLR3, the Myeloid differentiation primary response 88 (Myd88) and TIR-domain-containing adapter-inducing interferon-β (TRIF) cascades are activated and lead to a recruitment of IRFs as well as nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells (NF-κB) into the nucleus enhancing type III interferon expression (31). Notably, the combined activation of both IRFs and NF-κB was reported to be required for maximal IFNλ gene expression (32). While these pathways similarly induce type I and type III IFNs, KU-70, known as cytosolic DNA sensor, was found to rather induce type III interferon gene expression (33). The downstream mediator of KU-70 dependent IFN type III production was recently identified to be STING (Stimulator of IFN genes), which is also important in IFN type I signaling (34).

Except interferons, the pathogenesis of HRV infection involves various different cell types and cytokines as well as chemokines. Besides a direct effect on the airway epithelial cells that has been described, RV is causing a destruction of the tight junctions (35, 36). The infected epithelial cells and the neighbouring epithelium produce different cytokines and chemokines like IL-8, IP-10, G-CSF and RANTES (37). These mediators can also trigger an aggressive pro-inflammatory immune response that damages the epithelium. Additionally, it was demonstrated that TH2 cytokine driven mucus cell metaplasia reduced the virus load in human bronchial epithelial cells. The main target of the rhinovirus are the ciliated cells of the epithelium. Their infection leads to an even higher impairment of ciliary transport in asthmatics and a worsened clearance of mucus in the lung (38, 39). The antiviral immune response triggered by HRV can be divided further into an innate and an adaptive immune response. Aab et al. reported that in vitro B cell infection by HRV resulted in B cell proliferation, generation of infectious virions and the elicitation of pro-inflammatory cytokine production (40). Further, replication of HRV in human macrophages was shown to induce pro-inflammatory cytokine production via upregulation of NF-κB (41). Rajput et al. recently investigated the differences of RV-A1B and RV-C15 infections in asthmatic mice. They discovered higher expression of TH2 mediators (IL-5, IL-13 and CCL24), as well as higher peribronchial levels of IL-25, IL-33 and TSLP which are key drivers of ILC2 differentiation. As expected these effects resulted in higher numbers of ILC2 (42). This new insight supports the hypothesis that different RV subtypes show varying effects on the host and affect asthmatic patients more or less strongly.

The discovery of type III Interferons known as IFN-lambda in 2003 revised our knowledge about viral defense and led to a better understanding of the innate and adaptive immune response. So far, many studies and reports revealed the antiviral, anti-proliferative and immunomodulatory properties of type III IFN (27, 43–45). IFNλ family consist of four members (IFNλ 1-4) in humans and binds to the heterodimeric IFNλ receptor. IFNλ was shown to be predominantly produced upon infection at the site of entry in the epithelium of the lung or gut (46). Odendall et al. suggest that upregulation of peroxisomes during cell differentiation is a possible mechanism of preferential IFNλ production over IFNα in epithelial cells. RLRs drive the activation of IFNλ but not IFNα production via peroxisomal MAVS (47, 48). After the first contact of the pathogen with the epithelium the dendritic cells encounter antigen and rapidly produce IFNα as well as IFNλ (49). In the lung IFNλ is induced rapidly upon infection to control virus replication without activating inflammation. Subsequently IFNα levels increase and support immune defense while also inducing a pro-inflammatory response (50). Furthermore, there is evidence for a cross-talk between the type I and type III IFNs. Addition of IFNλ to human PBMC plus hepatoma cells co-culture increased the production of IFN type I and II (51). Similarly, pDC were also activated to produce IFNα upon IFNλ stimulation, as they highly express IFNλR.

In asthma, type III Interferons have been reported to decrease IL-4 and IL-5 production, as well as IL-13 production by T cells (3, 44, 52) providing evidence for a protective role in asthma exacerbations.

We and other groups demonstrated the protective role of IFN type III in experimental allergic airway disease (53). Here, balb/c wild-type mice were sensitized and challenged with ovalbumin (OVA) and additionally treated with recombinant IFNλ2 (IL-28A) or PBS intranasally. IL-28A-treated asthmatic mice had less granulocytes in the bronchoalveolar lavage (BAL), less inflammation in histological sections but higher IFNγ expression in OVA-restimulated cells isolated from the mediastinal lymph-node cells. Consistently, IFNLR1 KO asthmatic mice had higher IgE-levels, more granulocytes in the BAL and higher effector T cell responses in OVA-restimulated cells from the mediastinal lymphnode. Furthermore, this study demonstrated an immune shift from TH2/TH17 immune response to TH1 immune response following IL-28A application. The TH1 response was predominantly mediated by conventional dendritic cells via IFNγ ( Figure 2 , right-handside) (53). In a murine rheumatoid arthritis model, IFN λ2 treatment lead to reduction of IL1β, IL17 and IL23 mRNA expression in the joint. The numbers of neutrophils, TH17 and γδ T cells in the joint were similarly decreased. The data shows a limitation of neutrophil migration to the joint by IFNλ2 treatment (54). Another group also showed that IFNλ1 modulates TH1 and TH2 responses in a dose dependent manner. IL-13 secretion was markedly reduced while IFNγ could be induced by high doses only. Moreover, pretreatment of mDC with IFNλ1 prevented the activation of IL-13 producing T cells (55). This modulating effect on T cells was not only restricted to cytokine production (56). IFNLR1 KO mice showed a deficiency in memory T cells during influenza-A virus (IAV) infection. This effect is due to an altered migratory and antigen presentation ability of CD103+ DC (57). Both, IFNλ1 and IFNλ4, even have synergistic effects with low dose TCR-mediated stimulation and were able to enhance IFNγ production by CD8+ T cells (58). Further, peripheral DC stimulated with IFNλ upregulated CD80 and ICOS-L expression and, in combination with IFNα, an even stronger enhancement of CD80, CD83 and ICOS-L was observed (59).

These findings show that IFN type III not only modulates the T cell response directly but also indirectly via dendritic cells. During viral infections, IFNλ shows direct effects on epithelial cells ( Figure 2 , left handside). Remarkably, it also alters the immune response indirectly via the IFNλ-TSLP-axis. Thymic stromal lymphopoietin (TSLP), a regulator of adaptive immunity produced by epithelial cells was found to be induced by type III interferons after infecting mice with a live-attenuated influenza virus. TSLP stimulated migratory dendritic cells and boosted antigen-dependent germinal center reactions in draining lymph nodes. Furthermore, this resulted in higher numbers of virus-specific CD8+ T cells and an enhanced production of IgG1 and IgA. This study demonstrates a clear modulation of the adaptive immune system via type III interferons (60).

It was generally an assumed concept that subjects with underlying lung pathological conditions like asthma have a deficient innate immune response to infections, with significant downregulation of type I and III interferon genes (61–63). The role of type III IFNs in viral infections has been largely studied, unfortunately with mixed results so far. In the following section we discuss the results on IFNλ production in asthmatic patients in the lung during acute exacerbation or steady state asthma.

The effect of Type I and Type III IFN in the airways and the peripheral blood is dependent not only on its stability or production but also on the regulation of its receptor which at the end sequestrates free IFNs. Thus, another variable that must be considered is the regulation of IFN receptors in health and disease. The interferon-lambda receptor (IFNλR) consists of two subunits: the more restricted interferon-lambda receptor 1 (IL-28 Rα) and the ubiquitously expressed IL-10 receptor subunit beta (IL-10Rβ). Interferon-lambda family members binding to their receptor leads to the activation of Janus kinase 1 (JAK1) and Tyrosine kinase 2 (TYK2). This in turn results in the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2 heterodimers, which afterwards form a complex with IFN regulatory Factor 9 (IRF9). This STAT1-STAT2-IRF9 (ISGF3) complex translocates into the nucleus, inducing several hundreds of IFN-stimulated genes (ISGs). In the literature, the involvement of TYK2 in type III interferon signaling is discussed controversially due to reports that Tyk2 deficiency didn´t abolish IFNλ signaling (100).

IFNλR is expressed more selectively as other IFN receptors. The primary binding of IFNλ happens at the epithelial barrier in the lung and gut on epithelial cells. Immune cells have generally lower levels of IFNλR. B cells, CD4+ and CD8+ T cells express IFNλR while monocytes and NK cells only show low levels of expression (101). Plasmacytoid DC express a basal level of IFNλR that can be upregulated upon activation by viral stimuli (59). Recent publications found responsiveness of neutrophils from the bone marrow, blood and peritoneum to interferon-lambda. IFNλ reduced reactive oxygen species (ROS) production by regulating AKT via JAK2 (102). For NK cells there are also reports that find expression of IFNλR in murine and human NK cells or state indirect effects of IFNλ on NK cells (103). The IFNλR KO strain showed higher tumor metastasis in a model of lung cancer. When NK cells where transferred into these mice this effect could be diminished, suggesting the importance of IFNλ in normal NK cell function (104). B cells were also found to carry the IFNλR and were activated by IFNλ and TLR7/8 co-stimulation (105). So far it still remains controversial which immune cells are responding to IFNλ and if that is only the case during pathological processes and infections or also in homeostatic state.

The regulation of the IFNλR plays a central role in controlling resistance against viruses (106). Thus, regulation of the expression of this receptor by both genetic variability and pathogens might influence the functionality of the host defense. Furthermore, biological variation of IFNλR has an impact on the functionality and ability to activate its signaling cascade. This section details recent findings elucidating how the IFNλR expression and function are modulated.

Genetic variation in the form of several single nucleotide polymorphisms (SNPs) in the IFNλ and IFNλR gene region have been described in the literature so far. These SNPs have been associated with a series of important clinical phenotypes in the context of infectious disease (107).

One report found that a SNP in the IFNλR gene led to early treatment failure in HCV patients suggesting the influence of IFNλR on the outcome of therapeutic measures in virus infections (108). Another study showed that eosinophil numbers in the blood were variable due to IFNλR mutations in allergic rhinitis patients. However, no association between SNPs in the IFNλR gene and IgE serum levels was detected (109).

Epigenetic differences between individuals can also be the cause for variations in the expression of IFNλR and the unresponsiveness of cells in the presence of IFNλ. Ding et al. demonstrated that histone deacetylation-mediated closed chromatin conformation and hypermethylation are involved in the silencing of IFNλR expression (110). Methylation of the IFNλR1 gene in human gastric tumor cells and inhibition of methyltransferase lead to increased responsiveness to IFNλ during infection with human norovirus (111).

The detection of a soluble form of the IFNλR (sIFNλR) that compared to the membrane-bound (memIFNλR) form equally strongly binds to IFNλ was surprising. However, this soluble IFNλR fails to respond to its ligation due to the lack of the intracellular signal transduction. This soluble form could indicate a negative feedback regulation. Witte et al. further analyzed the soluble IFNλR and characterized it as a shorter, secreted form of the memIFNλR. It is missing the transmembrane and intracellular domain encoding parts and is equivalent to the extracellular domain of memIFNR except for the five C-terminal amino acids (112). Others hypothesized that there are different splice variants of the IFNλ receptor that have an impact on the potency of its antiviral response (101).

The sIFNλR form is a potential explanation for impaired IFN signaling in some patients. Investigation of this soluble version is still in its infancy, but has the potential to revolutionise our knowledge of IFNλ dependent viral defense. This underlines the need for more research on the soluble form of IFNλR and different splice variants, as well as gene mutations.

At present, the treatment of asthmatic patients focuses on controlling asthma symptoms and reducing future exacerbations. Glucocorticoids and bronchodilators remain the most prescribed therapy. Last years a novel strategy from GINA (Global Initiative for Asthma) was introduced, recommending a low-dose glucocorticoid and a long-acting beta agonist even in intermittent asthma. The goal is to reduce the chronic inflammation and future exacerbations, as enough data suggests even in mild forms of asthma (113). Subcutaneous immunotherapy in patients with allergic asthma may be beneficial too and should be considered, especially if patients have allergic rhinitis combined with asthma. In contrast, the sublingual immunotherapy has only modest results in asthmatic patients (114).

Type I interferons are already used in therapy up to date. IFNα is a possible treatment option for hepatitis C and B, malignant melanoma and Kaposi-syndrome. IFNβ is a therapeutical approach for multiple sclerosis. Unfortunately, these agents lead to severe side effects like transient changes in peripheral blood or influenza-like symptoms (fever, muscular pain) (115). These IFN type I members are also approved as therapeutic drugs in their PEGylated form. Currently there are also trials of treating COVID-19 patients with IFNα2a that lead to reduced CT scores and accelerated viral clearance (116).

Type III Interferon as a therapeutic agent in asthmatic patients may be of some interest during episodes of exacerbation. In airway epithelial cells, the type III IFN induce the expression of sets of ISGs that are similar to type I IFN, but the kinetic is slightly delayed and has a longer duration in comparison to type I IFN signaling. This could mean a potential clinical use of type III IFNs in preventing excessive antiviral and pro-inflammatory response during viral infections, with only local effects and less generalized damage. As shown in the study conducted by Klinkhammer et al., preventive treatment with IFNλ in mice inhibited the viral replication in the respiratory tract and conferred long-lasting antiviral protection in the upper airways, limiting the transmission to naïve contacts, too (117). Other preclinical studies in mice where intranasal IFNλ was administered demonstrated an improvement in lung inflammation (lower IL-4, IL-5, IL-13 and IL-33) and decrease in eosinophilia (44, 118).

Toll like Receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) expressed on infectious agents, like respiratory viruses and induce the development of antiviral and antibacterial immunity. TLRs7 and 8 are located in intracellular compartments of different cell types, predominantly dendritic cells and epithelial cells. Here they detect ssRNA particles from RNA viruses. Upon binding, TLR 7 and 8 lead to activation of the MyD88 signaling pathway via IRAK1 (interleukin-1 receptor-associated kinase 1) and IRAK4, resulting in the production of IFN Type I as well as pro-inflammatory cytokines ( Figure 1B ).

Recently, our group found that the toll-like receptor 7 and 8 (TLR7/8) agonist R848 (Resiquimod) induces IFNλR mRNA expression in peripheral blood mononuclear cells (PBMC) of healthy and asthmatic children. By contrast it downregulates the expression of IFNαR1 in PBMC. R848 also induced the levels of immunosuppressive IL-10 and the immunostimulatory cytokine IL-27 (119). These results suggest that the expression of INFλR can be modulated via TLR7 and 8. Other working groups hypothesized that SOCS-1 is able to utilize TLR8 to supress TLR7 mediated IFN production in mice (120). Therefore, despite differences in TLR7/8 between human and mouse, the activation of TLRs is not necessarily positive for infection control and immune defense.

Conversely, to the production of pro-inflammatory mediators, experimental studies have revealed a protective effect of R848 in experimental asthma. The numbers of cells in the bronchoalveolar lavage, as well as IgE, IL-4 and IL-5 levels were reduced in mice treated with Resiquimod before challenge (121–125). Grela´s group demonstrated that some of these effects can be transferred by treating invariant NKT cells with R848, and injecting them intra veniously to sensitized mice before challenging them (124). Furthermore, Jha et al. tested an R848-containing nasal spray in healthy, allergic, and allergic asthmatic patients. They discovered higher levels of IFNα, as well as pro-inflammatory cytokines in the nasal mucosal fluid after treatment in both allergic groups compared to healthy controls. A systemic activation of the immune response was not observed. The R848 treatment of the patients in this cohort was very well tolerated and helped to induce a better antiviral immune response (126). A report also stated that R848, in synergy with a TLR3 agonist, activates the production of type I and III interferons by monocyte derived dendritic cells (125).

In summary, these findings reveal TLR7/8 agonists as a potential target to modify the IFN type I and type III dependent immune responses ( Table 1 ). As some cell types are not responsive to IFNλ alone it might be a possible co-treatment option to induce IFNλR expression by giving TLR7/8 agonists. R848 is even a potential candidate as adjuvant used in vaccinations. There are already promising results in influenza vaccines that will be explored further in the future (127, 128).

Taken together, we need to improve the understanding of the interactions between viral infections and Type III Interferons, in order to prevent and treat exacerbations in asthma successfully. The emerging type III IFN therapies are promising and can lead to an individual and more specific treatment of exacerbations.

Reflecting on the discovery of interferons over the last 20 years has majorly advanced our understanding of virus resistance. As virus infection can induce exacerbations in asthmatics associated with increased disease severity, this review focuses on the mechanisms of interferon immune response in asthmatic patients, especially children. The literature on this topic remains very inconsistent and the methods employed do not always allow direct comparison of results. So far it hasn´t been proven that asthmatics have an impaired interferon response. However, there is emerging evidence that their viral clearance differs from that of healthy subjects. Some SNPs also suggest a connection between genetic mutations in the interferon-lambda gene and the development of autoimmune diseases. Modulation of the IFNλR via TLR7 and 8 agonists provides a means of interfering with the viral defense process. Moreover, the finding of a soluble IFNλR form raises new questions in this field that need to be investigated in greater depth.

The COVID-19 pandemic is a harsh reminder of the necessity of a solid viral defense line. A recent phase II clinical trial highlights the therapeutic potential of IFNλ response, using Peginterferon-lambda to treat COVID-19 patients, based on the assumption that interferons are the first combatants in the clearance of SARS-CoV-2, not only in the lung, but also in the whole organism (129). Nevertheless, we are only beginning to understand the possibilities inherent in altering the IFNλ response and the potential impact on our patients.

SK and CS wrote the manuscript, designed the figures and reviewed the current literature. SK and CS contributed equally to the manuscript and thus share the first authorship. JG wrote the paragraph on rhinovirus infection and antiviral immune response and created Figure 1A . SZ helped by providing clinical expertise on the literature. MC helped by providing expertise on the literature of IFNλ in the gut. SF supervised the work and edited the manuscript for submission. All authors contributed to the article and approved the submitted version.

SK is supported by the Interdisciplinary Center for Clinical Research (IZKF) at the University Hospital of the University of Erlangen-Nuremberg (Project A82). This work was supported by a grant, awarded to SF, from the Collaborative Research Centre (CRC) 1181 for the project TP-B08 N (Molecular mechanisms controlling regulatory T cell activation in the resolution of asthma), at the University hospital in Erlangen, Germany.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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