Role of the B7 family members in asthma.
Abstract
It is well established that allergic asthma is T cell-driven disease where CD4+ T cells of Th2 phenotype play a critical role in disease initiation and maintenance. There are several critical steps in the induction of Th2 type immune response to the allergen. The first critical step is the antigen processing and presentation of allergen-derived peptides in the context of specific major histocompatibility Class II (MHCII) molecules by antigen-presenting cells (APC). Recognition of this complex by T cell receptor (TCR) and interaction of costimulatory ligands with corresponding receptors represents the second step in T cell activation. As the third part of optimal T cell differentiation, proliferation, and expansion, several cytokines, integrins, and chemokines get involved in the fine-tuning of DC-T cell interaction and activation. Multiple recent evidences point to the selected members of B7 and semaphorin families as important checkpoints providing a fine-tuning regulation of immune response. In this book chapter, we discuss the properties of costimulatory molecules and address their roles in allergic asthma.
Keywords
- asthma
- immune response
- costimulation
- immune checkpoints
- B7 family molecules
- semaphorins
1. Introduction
Allergic asthma is a Th2-driven, immunological chronic disease [1]. CD4+ T cells of Th2 phenotype secreting Th2 cytokines such as IL-4, IL-5, and IL-13 play a critical role in asthma initiation and propagation [2]. In this book chapter, we address the question of how different costimulatory molecules influence the allergic immune response which is central to asthma pathogenesis.
The initial step in the immune response is the antigen capture and processing by APC. APC subdivide into “professional” such as dendritic cells (DC), B cells, and macrophages, and “unprofessional” such as epithelial cells, fibroblasts, basophils, eosinophils, ILC2 (type 2 innate lymphoid cells), which normally have other functions in tissues and do not act as APC [3, 4, 5]. Antigenic epitopes derived from a captured allergen are presented to T cells in the context of specific MHC (human leukocyte antigen, HLA, for human cells) molecules [1]. This is the first signal for T cell activation, whereas a second signal is derived from costimulation where specific costimulatory molecules on APC interact with their receptors on T cells (Figure 1) [6]. The first signal alone does not lead to the immune response to allergen (Figure 1), it rather induces T cell unresponsiveness or “anergy” [6, 7].
The members of the B7 family are the most characterized immunomodulatory ligands that bind to receptors on lymphocytes. They can act as costimulators or inhibitors/checkpoints. Currently, there are eleven known representatives of the B7 family, namely: B7–1 (CD80), B7–2 (CD86), B7-H1 (PD-L1, CD274), B7-DC (PDCD1LG2, PD-L2, CD273), B7-H2 (B7RP1, ICOS-L, CD275), B7-H3 (CD276), B7-H4 (B7x, B7S1, Vtcn1), B7-H5 (VISTA, Platelet receptor Gi24, SISP1), B7-H6 (NCR3LG1), B7-H7 (HHLA2), and ILDR2 (the synonyms of IChM names of the B7 family are given in parentheses) [7, 8]. Two molecules of B7 family proteins [9], B7–1 and B7–2, are the best characterized costimulators [7, 8]. Their ligation of CD28 expressed on T cells leads to T cell activation whereas interaction with cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) functions as an inhibitory signal.
Multiple recent reports pointed to selected semaphorin family [10, 11] members acting as checkpoints in the immune response regulating optimal T cell activation and cytokine production [10, 12]. Semaphorins alone are unable to induce or suppress T cell activation regulated by a combination of signals 1 and 2 but can significantly potentiate or downregulate it [10, 12]. Moreover, their involvement in asthmatic disease development has been supported by several recent publications (reviewed in [13, 14, 15] establishing them as potential immunomodulatory targets.
The goal of this book chapter is to discuss the roles of these molecules in asthma and provide the ground for their therapeutic use in disease prevention, management, or treatment.
2. B7 family members in asthma
2.1 B7: 1 and B7: 2
Asthma is Th2 cell-driven disease with Th2 type cytokines such as IL-4, IL-5, and IL-13 driving the disease pathology [2]. The effect of costimulation in asthma has been a subject of several decades’ of research. The differential role of two B7 family members in allergic response has been extensively studied and described in multiple articles published in the late 1990-s (16–19, reviewed in 20, 21). The work by Freeman et al. [16] questioned the functional necessity of two known at that time B7 family members. Using the
2.2 B7-H1 (PD-L1) and B7-DC (PD-L2)
The B7 homolog 1 (B7-H1) shares the same inducible PD-1 receptor on T cells with B7-DC (reviewed in 20, 21). While B7-H1 is constitutively expressed on monocytes and is downregulated with cell activation, B7-DC expression is induced by cell activation (reviewed in 7, 8, 20). Functionally, it was speculated that PDL-1 may suppress Th1-mediated inflammation and PDL-2 may suppress Th2-mediated inflammation (Figure 2) [20, 21]. The expression and regulation of PD-L1 and PD-L2 in asthma were analyzed using a segmental challenge of human lungs with allergen followed by BAL [22]. This study was initiated to clarify the importance of these costimulators in human asthma as previous reports using mouse models of the disease gave conflicting results [23, 24, 25]. The mouse lung expression levels of PD-L1 and PD-L2 were significantly upregulated by the OVA challenge [25]. However, the treatment of DC with CPG DNA, CD40L, GM-CSF, LPS, and IFN-γ led to the increased expression of PD-L2 on the cell surface whereas IL-4 and IL-13 induced the highest PD-L2 expression on DC among all mentioned above stimuli [25]. Interestingly, Th2 cytokines induce PD-L2 expression on DC but not B7–1 or B7–2 expression suggesting a regulatory role of this costimulatory in Th2 cell activation.
2.3 B7-H2 and ICOS
Another pair of the B7 family ligand and its receptor involved in the regulation of T cell activation comprises of B7-H2 and ICOS (Inducible CO-Stimulator) (Figure 2). It was originally shown that the engagement of ICOS by B7-H2 on CD4+ T cells increased the production of Th1 (IFN-γ and TNFα) and Th2 (IL-4, IL-5, and IL-10) cytokines [28, 29, 30]. ICOS-deficient mice were unable to induce the allergen-specific IgE responses when compared to WT mice which demonstrated an important role of ICOS:B7-H2 interaction in the induction of IgE production [31]. It was shown recently that the injection of anti-B7-H2 mAb resulted in the reduction of inflammation and Th2 cytokines production in the mouse model of allergic asthma [32]. Moreover, blocking the ICOS:B7-H2 interaction on human ILC2s reduced AHR and lung inflammation in the experimental asthma model [33]. In addition, it was demonstrated that in contrast to wild-type counterparts, B7-H2 deficient mice did not develop AHR after OVA sensitization and challenge [34].
2.4 B7-H3 and other B7-H molecules
To investigate the contribution of B7-H3 to the development of allergic asthma, mice were treated with antiB7-H3 blocking Ab during the course of OVA sensitization and challenges [35]. Anti-B7-H3 mAb treatment of mice at the experimental asthma induction phase (days 7–18 after allergen priming) suppressed allergic lung inflammation including eosinophilic infiltration, airway mucus hypersecretion, downregulated the number of B7-H3+ cells in the lung tissues as compared with the immunoglobulin G (IgG) treated control group. In addition, anti-B7-H3 mAb inhibited IL-4 and IL-17 levels and increased the expression IFN-γ in BALF of allergen-treated mice. However, anti-B7-H3 mAb treatment did not show an inhibitory effect on any measured asthma parameters at the effector phase (days 21–27 after priming). Nevertheless, B7-H3 blockage can provide a novel therapeutic approach for allergic asthma especially if used in a combination with immunotherapies that work in the effector phase. Two years later the same group of scientists reported an association of asthma exacerbation with increased levels of B7-H3 expression in the peripheral blood of asthmatic children which was significantly decreased by the use of steroids [36]. Their further studies in an animal model of asthma showed that recombinant B7-H3 administration to the mouse lungs in the time-frame of allergen priming (days 0 to 14), but before challenge (days 21, 27), significantly upregulate all parameters of allergic response such as inflammatory cell infiltration to the lung tissues, Th1 and Th2 cytokine levels in BAL and plasma, allergen-specific IgE production, and Th2/Th17 cell proliferation and cytokine levels [37].
The roles of other B7 family members such as B7-H4, B7-H5, and B7-H7 in asthma have never been investigated. Conflicting data on B7-H7 costimulation results led to a proposed concept of dual functionality as it is in the case of B7–1/B7–2 and CD28/CTLA-4. As an example, B7-H7 receptor CD28H could serve as an immunostimulatory receptor for T cell activation whereas KIR3DL3 could inhibit immune responses upon ligation of B7-H7 [38]. On the other hand, CD28H which is a CD28 homolog absent in mice but present in human serves as a functional receptor for B7-H5 [39]. B7-H5/CD28H interaction selectively costimulates human T-cell growth and cytokine production via an AKT-dependent signaling cascade. Interestingly, CD28H is constitutively expressed on all naïve T cells and its expression decreased with cell activation and is lost on terminally differentiated effector CD45RA + CCR7 − T cells [39]. Basically, the effector cytokine-producing CD4+ T helper cells and FoxP3+ CD4+ T reg cells lack CD28H expression. The authors associate such loss of expression for effector cells with repetitive cell stimulation. Moreover, the pattern on B7-H5 expression in peripheral tissue suggests that B7-H5/CD28H interaction is critical for the co-stimulation of newly generated effector or effector/memory T cells at the periphery. B7-H6 was not detected in normal human tissues but was expressed on human tumor cells [40]. B7-H6 triggers NKp30-mediated activation of human NK cells [40]. In summary, the roles of B7-H4, B7-H5, B7-H6, and B7-H7 in allergic asthma are long overdue to be determined.
2.5 ILDR2 in the immune response
Ildr2 (Ig-like domain-containing receptor 2), the gene encoding the murine ortholog (formerly designated “Lisch-like”) was originally identified as a modifier of susceptibility to type 2 diabetes in obese mice [41]. Its expression level was associated with reduced β- cell number and reproduction and with persistent mild hypoinsulinemic hyperglycemia [41]. A new immunomodulatory function of this B7-like homolog protein has been recently reported by Hecht and associates [42]. They showed that the administration of a recombinant ILDR2-mFc protein to mice displayed a therapeutic effect in a model of rheumatoid arthritis. It induced an increase in the IgG1/IgG2a ratio which suggested a shift from the proinflammatory pro-rheumatic Th1 responses to anti-inflammatory Th2 responses. The ILDR2 upregulation was reported previously for DC cultures when they were stimulated to become DC2-like cell that promotes Th2 response [43]. Therefore, ILDR2 has a promoting effect on allergic diseases, however, it has never been investigated directly.
3. Neuroimmune semaphorins in asthma
Several neuronal guidance proteins, known as semaphorin molecules, function in the immune system. This dual tissue performance has led to them being defined as “neuroimmune semaphorins” [44]. They have been shown to regulate T cell activation by serving as immune checkpoints (Figure 3) [12]. Neuroimmune semaphorins are either constitutively or inducibly expressed on immune cells. The T cell co-stimulatory action of neuroimmune semaphorins requires the presence of two signals: signal one provided by TCR/MHC engagement and signal two arises from B7/CD28 interaction. Thus, neuroimmune semaphorins serve as a “signal three” for immune cell activation by supporting their polarization, expansion, differentiation, and regulating the intensity of immune response. This book chapter summarizes the current knowledge on the structure and receptors for several neuroimmune semaphorins involved in the immune response and their role in allergic asthma.
3.1 Sema3A and Sema3E
Sema3A, previously known as chick collapsin 1, SemD, or Sema III, was discovered in the 1990s. In the nervous system, it functions either as a repulsive agent for axonal outgrowth or an attractive agent for apical dendrite growth [45, 46, 47, 48]. Sema3A is a glycoprotein with an Ig-like C2-type domain, a PSI (cysteine-rich module in extracellular portion) domain, and a Sema domain. Antipenko and associates [49] reported the crystal structure of Sema3A and identified a neuropilin (NRP) binding site and a potential plexin interaction site. Further studies demonstrated the physiologic receptors for Sema3A which consist of NRP/Plexin complexes where NRP1 serves as a ligand-binding receptor whereas Plexin A1 functions as a signaling receptor [50, 51]. The secreted 95 kDa forms of Sema3A can further undergo a proteolytic cleavage forming the 65 kDa forms [49], which have decreased activity toward neurons [52, 53]. The cryoEM of extracellular complex of Sema3A, PlexinA4, and NRP1 at 3.7 Å resolution demonstrated a large symmetric 2:2:2 molecular assembly in which each subunit makes multiple interactions with others [54].
The immunomodulatory role of Sema3A in allergic asthma has been extensively studied by the laboratory of Dr. Vadasz at Technion, Israel [55, 56, 57]. When examining the serum levels of Sema3A in asthmatic patients with different stages of disease severity they have determined that Sema3A was significantly downregulated in both severe and moderate asthmatic patients when compared to that of healthy individuals [55]. Low levels of Sema3A correlated with asthma severity. Purified CD4 + T cells from asthmatic patients were incubated with recombinant human (rh) Sema3A protein for 24 h what led to a higher number of Treg cells as compared to similarly conditioned cell cultures from healthy controls [55]. Moreover, rhSema3A affected Treg cells directly by inducing a higher Foxp3 expression. Considering the results of these clinical studies and established downregulatory role of Treg cells in asthma, it is logical to conclude that Sema3A plays an inhibitory role in allergic disease in part by inducing and stabilizing Treg cells. Indeed, the low expression of Sema3A was noticed in the nasal epithelium in the animal model of allergic rhinitis as compared to control mice [58]. Re-introduction of recombinant Sema3A to the mouse nose alleviated sneezing and nasal rubbing symptoms in allergic mice. When rhSema3A was administered intraperitoneally to the mice treated with allergen, a downregulation of lung inflammatory response and angiogenesis was observed [56, 57]. However, the full understanding of the mechanisms of lung inflammation and angiogenesis suppression by Sema3A is still ill-defined. In summary, these experiments indicated that sema3A is a potential novel therapeutic agent for the treatment of bronchial asthma.
Sema3E (originally termed M-SemaH) was first identified in the metastatic cell lines using a differential display technique which allowed to identify 2 splice variants encoding the same 775 a.a. protein [59]. The protein consists of a putative signaling sequence in NH- terminus followed by a large semaphorin domain, a c2 immunoglobulin-like domain at the amino acids 595–659, approximately 20 residues serving as a transmembrane domain, and positively charged residues in the COOH-terminus [59]. Sema3E contains 13 conserved cysteine residues and 3 potential A’-glycosylation sites. The amino acid sequence of Sema3E was found to be 82% identical to the reported partial sequence of chick collapsin 5 and 44–48% to all other members of the subclass III of the family [59]. Also, the AU-rich motif (AUUUA) conferring protein instability has been defined.
The extensive work by Movassagh and associates from the laboratory of Dr. Gounni at the University of Manitoba, Canada [60] defined the effect of Sema3E deficiency in experimental mouse model of asthma. Such deficiency resulted in substantial airway eosinophilia in untreated Sema3E−/− mice whereas the numbers of alveolar macrophages, T, B, NK, and NKT cells were comparable to those in WT mice. Therefore, the absence of Sema3E predisposed mice to allergic inflammation. Indeed, repeated inhalational exposure to HDM increased many components of asthmatic response in Sema3E−/− mice. This increase involved peribronchial inflammation, AHR to methacholine challenges, goblet cell hyperplasia, collagen deposition, and Th2/Th17 cytokine levels. All these features of asthmatic response were significantly downregulated when recombinant Sema3E was administered to the allergen sensitized mice intranasally [61]. A higher frequency of CD11b + pulmonary DC, a Th2- promoting subtype of DC, was observed in Sema3E−/− mice in both, the steady-state and allergen sensitized conditions as compared to WT control animals. When adoptively transferred to naïve mice, these Sema3E−/− CD11b + DC were able to induce the highest allergic lung inflammatory response especially when the DC recipients were Sema3E−/− mice. While examining the generated bone marrow chimeric mice, the authors defined the contribution of Sema3E on bone marrow-derived inflammatory cells in allergen-induced lung pathology. This work aligns with their previous study demonstrating Sema3E-mediated inhibition of human ASM cell proliferation and migration and defining the signaling pathways involved in such effect [62]. Moreover, their recent study clearly demonstrated a suppressed Sema3E expression in human severe asthma using bronchial biopsy and lung tissue histology specimens [63]. These data suggest that Sema3E plays an important regulatory role in allergic asthma. Targeting this molecule could be a novel approach to treat allergic asthma.
3.2 Sema4A and Sema4D
The Sema4A molecule is a 761 aa long glycoprotein of 150 kDa molecular weight with an NH2-terminal 32 aa signal peptide, a Sema domain, and an Ig domain of the C2 type (both 651 aa), a hydrophobic 21 aa transmembrane region, and a 57 aa cytoplasmic tail (Swissprot Accession # Q9H3S1). Its functions are the most complicated, diverse, and least studied. Sema4A has six known receptors (reviewed in 12). Sema4A exists in both membrane-bound and soluble forms [64, 65]. On the cell surface, it is expressed as a monomer and a dimer [65].
The role of Sema4A in asthma has been evaluated in the laboratory of Dr. Chapoval at the University of Maryland, USA [64, 66, 67]. It has been shown previously that lung-specific vascular endothelial growth factor (VEGF) expression induced asthma-like pathologies in the murine lungs [68, 69]. The experimental models of OVA-induced and VEGF-mediated allergic airway inflammation were used to assess the changes in expression of immune semaphorins and their receptors in mouse lung tissues [64]. We reported Sema4A expression was detected on bronchial epithelial cells, smooth muscle cells, and accessory-like cells. Both external allergen and lung local VEGF upregulated the expression of Sema4A and its receptors in the lung tissue. Allergen treatment led to a detection of a whole Sema4A protein plus its dimer in the bronchoalveolar (BAL) fluids under inflammation which was not found in the control mouse group.
A recent study by Lynch and associates [70] examined the role of Sema4A in respiratory syncytial virus (RSV)-induced bronchiolitis which is a predisposition for asthma. The authors used BDCA2-diphtheria toxin receptor (DTR) transgenic mice to induce the specific and reversible depletion of plasmacytoid DC (pDC) with intraperitoneal DT injections. They showed that pDC depletion in neonatal, but not adult, mice increased bronchiolitis severity and was sufficient to evoke an asthma-like phenotype upon viral challenge thus conforming that severe bronchiolitis in early life predisposes to subsequent asthma upon viral exposure. They also demonstrated that pDC from virus-infected mice expand Foxp3 + NRP1+ Treg cells and such expansion is effectively inhibited by the use of anti-Sema4A neutralizing Ab. Moreover, NRP1+ Treg cells transfer from infected to naïve mice prevents the recipients from viral bronchiolitis and subsequent asthma. This study further strengthens the importance of the Sema4A-mediated Treg cells expansion pathway and its important role in asthma protection and/or suppression.
Sema4D, also known as Cluster of Differentiation 100 (CD100), was the first semaphorin with defined expression and function in the immune system ([71, 72], reviewed in [12, 44, 73]). Several studies pointed to its critical regulatory role in the immune system ([74, 75], reviewed in [12, 44, 73, 76]). Sema4D consists of an NH2- terminal signal peptide, a sema domain, an Ig domain of the C2 type, a hydrophobic transmembrane region, and a cytoplasmic tail [71, 72]. The molecule’s crystal modeling demonstrates the presence of a conserved seven-blade β-propeller structure [77] which is the structure of a conserved sema domain and is shared by all semaphorin family members. There is an 88% amino acid identity between human and murine Sema4D homologs [72]. Sema4D exists in both, membrane-bound and soluble forms, which are both biologically active [78, 79].
The recent report from Dr. Chapoval’s laboratory at the University of Maryland has demonstrated an important regulatory role of Sema4D in asthma pathogenesis [80]. We exposed Sema4D-deficient and WT mice to OVA injections and challenges in the well-defined mouse model of OVA-induced experimental asthma. Sema4D-deficient mice demonstrated a significant decrease in eosinophilic airway infiltration after allergen challenge relative to WT mice. This reduced allergic inflammatory response was associated with decreased BAL Th2 and Th17 cytokine levels. The reduced T cell proliferation in OVA₃₂₃₋₃₃₉-restimulated Sema4D−/− cell cultures suggested lower T cell activation. Sema4D deficiency led to the increased number of Treg cells in mice after the allergen challenge. Surprisingly, Sema4D deficiency had no effect on airway hyperreactivity (AHR) to methacholine challenges in either acute or chronic experimental disease settings. Moreover, the lung DC number and activation were not affected by Sema4D deficiency. Our research data provided new insight into Sema4D biology and defined Sema4D as an important regulator of Th2-driven lung inflammation and as a potential target for disease immunotherapy.
3.3 Sema6D and Sema7A
Molecular cloning, mapping, and functional analysis of Sema6D together with Sema6C have been carried out more recently if compared to other semaphorins with costimulatory properties ([81], reviewed in [12]). Amino acid sequence alignment analysis of human semaphorin (HSA)SEMA6C, rat Sema6C, and mouse Sema6C showed the existence of the class VI semaphorin characteristic of the extracellular domain and PSI domain, which differ from all known members of semaphorin family. Predicted structure (HSA)SEMA6D isoforms were compared with related semaphorin proteins. Five isoforms of SEMA6D have been isolated and the significance of the alternatively spliced variants was evaluated by RT-PCR and Northern blots. The expression of different isoforms was found to be regulated in a tissue- and development-dependent manner. Sema6D consists of a signal peptide, a PSI domain, a transmembrane segment, an Ig domain, and a sema domain. Sequence analysis has shown that the translated polypeptides are composed of a 1–21 aa signal peptide followed by a 59–477 aa sema domain, a 508–563 aa PSI domain, a transmembrane segment, and a long cytoplasmic region.
The role of Sema6D in asthma has never been investigated. Based on the published data claiming a costimulatory role of Sema6D in T cell activation, we assume it regulates a disease severity. Regulation of T cell activation by Sema6D was examined
It is well established that macrophage polarization is a result of and a contributor to asthma pathogenesis [83]. Macrophages consist of more than 70% of lung cells and increased M2 macrophage polarization mirrored by increased Th2 response leads to further heightening of asthma pathology [83]. Macrophages and DCs expressed high levels of Sema6D [84]. Sema4D deficiency led to a downregulation of M2 polarization by bone marrow-derived macrophages accompanied by significant reductions in expression of Arg1, chitinase 3 like-1 (Chi3l1), Retnla, and Il10, as determined by qRT-PCR [84].
The cDNA clone containing the entire coding sequence of the Sema7A gene and its molecular characteristics were first reported by Yamada and associates [85]. The human Sema7A cDNA clones were identified through the screening of a plasmid library generated from a leukemic T cell line. The 1998-base pairs of the cloned DNA’s open reading frame encoded a 666 aa protein. This protein contained a 46 aa signal peptide and a 19 aa GPIanchor glycophosphatidylinositol linkage motif. The membrane-anchoring form of Sema7A was 602 aa long. The estimated molecular mass of the nonglycosylated form was 68 kDa. The authors located an “RGD (Arg-Gly-Asp) cell attachment sequence and the five potential N-linked glycosylation sites on the membrane-anchoring form”. The expression of a native Sema7A form in transfected cells was confirmed by immunoprecipitation and flow cytometry analyses of cell transfectants. The Sema7A gene was identified on chromosome 15 (15q23–24) by radiation hybrid mapping. The 88.0% similarity at the nucleotide level was detected between murine and human Sema7A or 89.3% similarity at the amino acid level of corresponding proteins [86]. Both human and mouse SEMA7A contain a seven-bladed β-propeller semaphorin N- terminus domain, a plexin, semaphorin, and integrin domain (PSI), an immunoglobulin-like domain, and the characteristic for this particular semaphorin molecule GPI anchor in their C-terminus [87].
The extensive examination of a costimulatory function of Sema7A in T cell proliferation established this neuroimmune semaphorin as an inhibitor of T cell activation [88]. Sema7A−/− T cells demonstrated an enhanced proliferation upon Ag re-stimulation
B7 family member | Role in asthma | Function | Reference |
---|---|---|---|
B7–1/B7–2 | Stimulatory | Stimulates T cell activation and inflammatory cytokines production | [17, 18] |
B7-H1 (PD-L1)/B7-DC (PD-L2) | Inhibitory | Downregulates inflammatory cytokines production and airway hyperreactivity | [22, 25, 26] |
B7-H2 | Stimulatory | Induces Th2 cytokines and IgE productions | [28, 29] |
B7-H3 | Stimulatory | Increases Th2 and Th17 cytokine production | [35, 36] |
B7-H4 | Unknown | ||
B7-H5 | Unknown | ||
B7-H6 | Unknown | ||
B7-H7 | Unknown | ||
ILDR2 | Stimulatory | Promotes Th2 response | [42, 43] |
Semaphorin | Role in asthma | Function | Reference |
---|---|---|---|
Sema3A | Inhibitory | Stimulates Treg cells. Low serum levels correlate with asthma severity Downregulates lung inflammatory response | [55, 56, 57, 58] |
Sema3E | Inhibitory | Sema3E deficiency upregulates asthmatic response, led to a high frequency of Th2 promoting DC. Sema3E inhibits ASM cell proliferation. Low lung tissue expression is associated with higher asthma severity. | [60, 61, 62, 63] |
Sema4A | Inhibitory | Sema4A deficiency led to increases in many asthma parameters. Recombinant Sema4A applications | [66, 67] |
Sema4D | Stimulatory | Sema4D deficiency led to a lower lung inflammatory response to allergen challenges, lower T cell activation, and increased number of Treg cells | [80] |
Sema6D | Unknown | ||
Sema7A | Inhibitory | Expressed on eosinophils. Regulates ASM contractility. Eosinophils are predominant source of Sema7A in the lungs. Lung Sema7A expression is upregulated by allergen bronchoprovocation | [89, 90] |
4. Conclusions
Analysis of costimulatory molecules critically involved in asthma, a chronic respiratory Th2-driven disease, will help us to underline the immune mechanisms of disease development and progression. A complete understanding of these mechanisms will guide the development of novel therapeutic strategies to combat asthma and related allergies. Studies aimed to characterize the functions of several B7 family members and semaphorin family members in allergic asthma are either incomplete or ongoing. Further studies of the interplays between different individual costimulatory pathways should provide clearer insights into the disease pathology and guide the development of precise therapeutics.
Acknowledgments
S.P.C is supported by SemaPlex LLC and by NIH/NIAID RO1 AI076736 and RO1 AI143845 grants where she is a co-investigator. A.I.C. is supported by the Ministry of Science and Higher Education of the Russian Federation grant No. FZMW-2020-0007.
References
- 1.
Chapoval SP, David CS. Identification of antigenic epitopes on human allergens: Studies with HLA transgenic mice. Environmental Health Perspectives. 2003; 111 (2):245-250 - 2.
Atamas SP, Chapoval SP, Keegan AD. Cytokines in chronic respiratory diseases. F1000 Biology Reports. 2013; 5 :3 - 3.
Tang ML, Khan MK, Croxford JL, Tan KW, Angeli V, Gasser S. The DNA damage response induces antigen presenting cell-like functions in fibroblasts. European Journal of Immunology. 2014; 44 (4):1108-1118 - 4.
Arebro J, Tengroth L, Razavi R, Kumlien Georén S, Winqvist O, Cardell LO. Antigen-presenting epithelial cells can play a pivotal role in airway allergy. The Journal of Allergy and Clinical Immunology. 2016; 137 (3):957-60.e7 - 5.
Schuijs MJ, Hammad H, Lambrecht BN. Professional and 'Amateur' antigen-presenting cells In type 2 immunity. Trends in Immunology. 2019; 40 (1):22-34 - 6.
Esensten JH, Helou YA, Chopra G, Weiss A, Bluestone JA. CD28 Costimulation: From mechanism to therapy. Immunity. 2016; 44 (5):973-988 - 7.
Chapoval AI, Chapova SP, Shcherbakova NS, Shcherbakov DN. Immune checkpoints of the B7 family. Part 1. General characteristics and first representatives: B7-1, B7-2, B7-H1, B7-H2, and B7-DC. Russ. Journal of Bioorganic Chemistry. 2019; 45 :225-240 - 8.
Chapoval AI, Chapova SP, Shcherbakova NS, Shcherbakov DN. Immune checkpoints of the B7 family. Part 2. Representatives of the B7 family B7-H3, B7-H4, B7-H5, B7-H6, B7-H7, and ILDR2 and their receptors. Russ. Journal of Bioorganic Chemistry. 2019; 45 :321-334 - 9.
Bhatia S, Edidin M, Almo SC, Nathenson SG. B7-1 and B7-2: Similar costimulatory ligands with different biochemical, oligomeric and signaling properties. Immunology Letters. 2006; 104 (1-2):70-75 - 10.
Kumanogoh A, Kikutani H. Roles of the semaphorin family in immune regulation. Advances in Immunology. 2003; 81 :173-198 - 11.
Yazdani U, Terman JR. The semaphorins. Genome Biology. 2006; 7 :211 - 12.
Chapoval SP. Neuroimmune semaphorins as costimulatory molecules and beyond. Molecular Medicine. 2018; 24 (1):13 - 13.
Yeganeh B, Xia C, Movassagh H, Koziol-White C, Chang Y, Al-Alwan L, et al. Emerging mediators of airway smooth muscle dysfunction in asthma. Pulmonary Pharmacology & Therapeutics. 2013; 26 (1):105-111 - 14.
Chapoval SP, Vadasz Z, Chapoval AI, Toubi E. Semaphorins 4A and 4D in chronic inflammatory diseases. Inflammation Research. 2017; 66 (2):111-117 - 15.
Kalmarzi RN, Rajabinejad M, Lotfi R. Immune semaphorins: Crucial regulatory signals and novel therapeutic targets in asthma and allergic diseases. European Journal of Pharmacology. 2020; 15 (881):173209 - 16.
Freeman GJ, Boussiotis VA, Anumanthan A, Bernstein GM, Ke XY, Rennert PD, et al. B7-1 and B7-2 do not deliver identical costimulatory signals, since B7-2 but not B7-1 preferentially costimulates the initial production of IL-4. Immunity. 1995; 2 :523-532 - 17.
Van Neerven RJ, Van de Pol MM, Van der Zee JS, Stiekema FE, De Boer M, Kapsenberg ML. Requirement of CD28-CD86 costimulation for allergen-specific T cell proliferation and cytokine expression. Clinical and Experimental Allergy. 1998; 28 :808-816 - 18.
Larche M, Till SJ, Haselden BM, North J, Barkans J, Corrigan CJ, et al. Costimulation through CD86 is involved in airway antigen-presenting cell and T cell responses to allergen in atopic asthmatics. Journal of Immunology. 1998; 161 :6375-6382 - 19.
Jaffar Z, Roberts K, Pandit A, Linsley P, Djukanovic R, Holgate S. B7 costimulation is required for IL-5 and IL-13 secretion by bronchial biopsy tissue of atopic asthmatic subjects in response to allergen stimulation. American Journal of Respiratory Cell and Molecular Biology. 1999; 20 :153-162 - 20.
Bellou A, Finn PW. Costimulation: Critical pathways in the immunologic regulation of asthma. Current Allergy and Asthma Reports. 2005; 5 :149-154 - 21.
Chen YQ , Shi HZ. CD28/CTLA-4--CD80/CD86 and ICOS--B7RP-1 costimulatory pathway in bronchial asthma. Allergy. 2006; 61 (1):15-26 - 22.
Bratke K, Fritz L, Nokodian F, Geißler K, Garbe K, Lommatzsch M, et al. Differential regulation of PD-1 and its ligands in allergic asthma. Clinical and Experimental Allergy. 2017; 47 (11):1417-1425 - 23.
Akbari O, Stock P, Singh AK, et al. PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions. Mucosal Immunology. 2010; 3 :81-91 - 24.
Matsumoto K, Inoue H, Nakano T, et al. B7-DC regulates asthmatic response by an IFN-gamma-dependent mechanism. Journal of Immunology. 2004; 172 :2530-2541 - 25.
Oflazoglu E, Swart DA, Anders-Bartholo P, Jessup HK, Norment AM, Lawrence WA, et al. Paradoxical role of programmed death-1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo. European Journal of Immunology. 2004; 34 (12):3326-3336 - 26.
McAlees JW, Lajoie S, Dienger K, Sproles AA, Richgels PK, Yang Y, et al. Differential control of CD4(+) T-cell subsets by the PD-1/PD-L1 axis in a mouse model of allergic asthma. European Journal of Immunology. 2015; 45 (4):1019-1029 - 27.
Froidure A, Vandenplas O, D'Alpaos V, Evrard G, Pilette C. Persistence of asthma following allergen avoidance is associated with proTh2 myeloid dendritic cell activation. Thorax. 2015; 70 (10):967-973 - 28.
Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I, et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature. 1999; 397 :263-266 - 29.
Coyle AJ, Lehar S, Lloyd C, Tian J, Delaney T, Manning S, et al. The CD28-related molecule ICOS is required for effective T cell-dependent immune responses. Immunity. 2000; 13 (1):95-105 - 30.
McAdam AJ, Chang TT, Lumelsky AE, Greenfield EA, Boussiotis VA, Duke-Cohan JS, et al. Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4+ T cells. Journal of Immunology. 2000; 165 (9):5035-5040 - 31.
Dong C, Juedes AE, Temann UA, Shresta S, Allison JP, Ruddle NH, et al. ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature. 2001; 409 (6816):97-101 - 32.
Uwadiae FI, Pyle CJ, Walker SA, Lloyd CM, Harker JA. Targeting the ICOS/ICOS-L pathway in a mouse model of established allergic asthma disrupts T follicular helper cell responses and ameliorates disease. Allergy. 2019; 74 (4):650-662 - 33.
Maazi H, Patel N, Sankaranarayanan I, Suzuki Y, Rigas D, Soroosh P, et al. ICOS:ICOS-ligand interaction is required for type 2 innate lymphoid cell function, homeostasis, and induction of airway hyperreactivity. Immunity. 2015; 42 (3):538-551 - 34.
Kadkhoda K, Wang S, Fan Y, Qiu H, Basu S, Halayko AJ, et al. ICOS ligand expression is essential for allergic airway hyperresponsiveness. International Immunology. 2011; 23 (4):239-249 - 35.
Chen ZR, Zhang GB, Wang YQ , Yan YD, Zhou WF, Zhu C, et al. Therapeutic effects of anti-B7-H3 antibody in an ovalbumin-induced mouse asthma model. Annals of Allergy, Asthma & Immunology. 2013; 111 (4):276-281 - 36.
Chen Z, Zhang G, Wang Y, Yan Y, Zhu C, Huang L, et al. B7-H3 expression in children with asthma exacerbation. Allergy and Asthma Proceedings. 2015; 36 (4):37-43 - 37.
Gu W, Zhang X, Yan Y, Wang Y, Huang L, Wang M, et al. B7-H3 participates in the development of asthma by augmentation of the inflammatory response independent of TLR2 pathway. Scientific Reports. 2017; 17 (7):40398 - 38.
Bhatt RS, Berjis A, Konge JC, Mahoney KM, Klee AN, Freeman SS, et al. KIR3DL3 is an inhibitory receptor for HHLA2 that mediates an alternative Immunoinhibitory pathway to PD1. Cancer Immunology Research. 2020; 9 (2):156-169 - 39.
Zhu Y, Yao S, Iliopoulou BP, Han X, Augustine MM, Xu H, et al. B7-H5 costimulates human T cells via CD28H. Nature Communications. 2013; 4 :2043 - 40.
Kaifu T, Escalière B, Gastinel LN, Vivier E, Baratin M. B7-H6/NKp30 interaction: A mechanism of alerting NK cells against tumors. Cellular and Molecular Life Sciences. 2011; 68 (21):3531-3539 - 41.
Dokmanovic-Chouinard M, Chung WK, Chevre JC, Watson E, Yonan J, Wiegand B, et al. Positional cloning of "Lisch-like", a candidate modifier of susceptibility to type 2 diabetes in mice. PLoS Genetics. 2008; 4 (7):e1000137 - 42.
Hecht I, Toporik A, Podojil JR, Vaknin I, Cojocaru G, Oren A, et al. ILDR2 is a novel B7-like protein that negatively regulates T cell responses. Journal of Immunology. 2018; 200 (6):2025-2037 - 43.
Gueguen C, Bouley J, Moussu H, Luce S, Duchateau M, Chamot-Rooke J, et al. Changes in markers associated with dendritic cells driving the differentiation of either TH2 cells or regulatory T cells correlate with clinical benefit during allergen immunotherapy. The Journal of Allergy and Clinical Immunology. 2016; 137 (2):545-558 - 44.
Nkyimbeng-Takwi E, Chapoval SP. Biology and function of neuroimmune semaphorins 4A and 4D. Immunologic Research. 2011; 50 (1):10-21 - 45.
Kolodkin AL, Matthes DJ, Goodman CS. The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell. 1993; 75 :1389-1399 - 46.
Luo Y, Raible D, Raper JA. Collapsin: A protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell. 1993; 75 :217-227 - 47.
Puschel AW, Adams RH, Betz H. Murine semaphorin D/collapsin is a member of a diverse gene family and creates domains inhibitory for axonal extension. Neuron. 1995; 14 :941-948 - 48.
Polleux F, Morrow T, Ghosh A. Semaphorin 3A is a chemoattractant for cortical apical dendrites. Nature. 2000; 404 :567-573 - 49.
Antipenko A, Himanen JP, van Leyen K, Nardi-Dei V, Lesniak J, Barton WA, et al. Structure of the semaphorin-3A receptor binding module. Neuron. 2003; 39 (4):589-598 - 50.
Takahashi T, Fournier A, Nakamura F, Wang LH, Murakami Y, Kalb RG, et al. Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors. Cell. 1999; 99 (1):59-69 - 51.
He Z, Tessier-Lavigne M. Neuropilin is a receptor for the axonal chemorepellent Semaphorin III. Cell. 1997; 90 :739-751 - 52.
Adams RH, Lohrum M, Klostermann A, Betz H, Puschel AW. The chemorepulsive activity of secreted semaphorins is regulated by furin-dependent proteolytic processing. The EMBO Journal. 1997; 16 :6077-6086 - 53.
Klostermann A, Lohrum M, Adams RH, Puschel AW. The chemorepulsive activity of the axonal guidance signal semaphorin D requires dimerization. The Journal of Biological Chemistry. 1998; 273 :7326-7331 - 54.
Lu D, Shang G, He X, Bai XC, Zhang X. Architecture of the Sema3A/PlexinA4/Neuropilin tripartite complex. Nature Communications. 2021; 12 (1):3172 - 55.
Cozacov R, Halasz K, Haj T, Vadasz Z. Semaphorin 3A: Is a key player in the pathogenesis of asthma. Clinical Immunology. 2017; 184 :70-72 - 56.
Toubi E, Vadasz Z. Semaphorin3A is a promising therapeutic tool for bronchial asthma. Allergy. 2020; 75 (2):481-483 - 57.
Adi SD, Eiza N, Bejar J, Shefer H, Toledano S, Kessler O, et al. Semaphorin 3A is effective in reducing both inflammation and angiogenesis in a mouse model of bronchial asthma. Frontiers in Immunology. 2019; 22 (10):550 - 58.
Sawaki H, Nakamura F, Aihara M, Nagashima Y, Komori-Yamaguchi J, Yamashita N, et al. Intranasal administration of semaphorin-3A alleviates sneezing and nasal rubbing in a murine model of allergic rhinitis. Journal of Pharmacological Sciences. 2011; 117 (1):34-44 - 59.
Christensen CR, Klingelhöfer J, Tarabykina S, Hulgaard EF, Kramerov D, Lukanidin E. Transcription of a novel mouse semaphorin gene, M-semaH, correlates with the metastatic ability of mouse tumor cell lines. Cancer Research. 1998; 58 :1238-1244 - 60.
Movassagh H, Shan L, Mohammed A, Halayko AJ, Gounni AS. Semaphorin 3E deficiency exacerbates airway inflammation, Hyperresponsiveness, and Remodeling in a mouse model of allergic asthma. Journal of Immunology. 2017; 198 :1805-1814 - 61.
Movassagh H, Shan L, Duke-Cohan JS, Halayko AJ, Uzonna JE, Gounni AS. Semaphorin 3E alleviates hallmarks of house dust mite-induced allergic airway disease. The American Journal of Pathology. 2017; 187 :1566-1576 - 62.
Movassagh H, Shan L, Halayko AJ, Roth M, Tamm M, Chakir J, et al. Neuronal chemorepellent Semaphorin 3E inhibits human airway smooth muscle cell proliferation and migration. The Journal of Allergy and Clinical Immunology. 2014; 133 (2):560-567 - 63.
Movassagh H, Shan L, Chakir J, McConville JF, Halayko AJ, Koussih L, et al. Expression of semaphorin 3E is suppressed in severe asthma. The Journal of Allergy and Clinical Immunology. 2017; 140 (4):1176-1179 - 64.
Smith EP, Shanks K, Lipsky MM, DeTolla LJ, Keegan AD, Chapoval SP. Expression of neuroimmune semaphorins 4A and 4D and their receptors in the lung is enhanced by allergen and vascular endothelial growth factor. BMC Immunology. 2011; 12 :30 - 65.
Toyofuku T, Yabuki M, Kamei J, Kamei M, Makino N, Kumanogoh A, et al. Semaphorin-4A, an activator for T-cell-mediated immunity, suppresses angiogenesis via Plexin-D1. The EMBO Journal. 2007; 26 (5):1373-1384 - 66.
Nkyimbeng-Takwi EH, Shanks K, Smith E, Iyer A, Lipsky MM, Detolla LJ, et al. Neuroimmune semaphorin 4A downregulates the severity of allergic response. Mucosal Immunology. 2012; 5 (4):409-419 - 67.
Mogie G, Shanks K, Nkyimbeng-Takwi EH, Smith E, Davila E, Lipsky MM, et al. Neuroimmune semaphorin 4A as a drug and drug target for asthma. International Immunopharmacology. 2013; 17 (3):568-575 - 68.
Lee CG, Link H, Baluk P, Homer RJ, Chapoval S, Bhandari V, et al. Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung. Nature Medicine. 2004; 10 :1095-1103 - 69.
Bhandari V, Choo-Wing R, Chapoval SP, Lee CG, Tang C, Kim YK, et al. Essential role of nitric oxide in VEGF-induced, asthma-like angiogenic, inflammatory, mucus, and physiologic responses in the lung. Proceedings of the National Academy of Sciences of the United States of America. 2006; 103 (29):11021-11026 - 70.
Lynch JP, Werder RB, Loh Z, Sikder MAA, Curren B, Zhang V, et al. Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a-mediated T reg expansion. The Journal of Experimental Medicine. 2018; 215 (2):537-557 - 71.
Hall KT, Boumsell L, Schultze JL, Boussiotis VA, Dorfman DM, Cardoso AA, et al. Human CD100, a novel leukocyte semaphorin that promotes B-cell aggregation and differentiation. Proceedings of the National Academy of Sciences of the United States of America. 1996; 93 (21):11780-11785 - 72.
Furuyama T, Inagaki S, Kosugi A, Noda S, Saitoh S, Ogata M, et al. Identification of a novel transmembrane semaphorin expressed on lymphocytes. The Journal of Biological Chemistry. 1996; 271 (52):33376-33381 - 73.
Suzuki K, Kumanogoh A, Kikutani H. CD100/Sema4D, a lymphocyte semaphorin involved in the regulation of humoral and cellular immune responses. Cytokine & Growth Factor Reviews. 2003; 14 (1):17-24 - 74.
Bougeret C, Mansur IG, Dastot H, Schmid M, Mahouy G, Bensussan A, et al. Increased surface expression of a newly identified 150-kDa dimer early after human T lymphocyte activation. Journal of Immunology. 1992; 148 (2):318-323 - 75.
Herold C, Bismuth G, Bensussan A, Boumsell L. Activation signals are delivered through two distinct epitopes of CD100, a unique 150 kDa human lymphocyte surface structure previously defined by BB18 mAb. International Immunology. 1995; 7 :1-8 - 76.
Kumanogoh A, Kikutani H. Biological functions and signaling of a transmembrane semaphorin, CD100/Sema4D. Cellular and Molecular Life Sciences. 2004; 61 (3):292-300 - 77.
Love CA, Harlos K, Mavaddat N, Davis SJ, Stuart DI, Jones EY, et al. The ligand-binding face of the semaphorins revealed by the high-resolution crystal structure of SEMA4D. Nature Structural Biology. 2003; 10 :843-848 - 78.
Elhabazi A, Delaire S, Bensussan A, Boumsell L, Bismuth G. Biological activity of soluble CD100. I. the extracellular region of CD100 is released from the surface of T lymphocytes by regulated proteolysis. Journal of Immunology. 2001; 166 :4341-4347 - 79.
Zhu L, Bergmeier W, Wu J, Jiang H, Stalker TJ, Cieslak M, et al. Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury. Proceedings of the National Academy of Sciences of the United States of America. 2007; 104 (5):1621-1626 - 80.
Shanks K, Nkyimbeng-Takwi EH, Smith E, Lipsky MM, DeTolla LJ, Scott DW, et al. Neuroimmune semaphorin 4D is necessary for optimal lung allergic inflammation. Molecular Immunology. 2013; 56 (4):480-487 - 81.
Qu X, Wei H, Zhai Y, Que H, Chen Q , Tang F, et al. Identification, characterization, and functional study of the two novel human members of the semaphorin gene family. The Journal of Biological Chemistry. 2002; 277 (38):35574-35585 - 82.
O'Connor BP, Eun SY, Ye Z, Zozulya AL, Lich JD, Moore CB, et al. Semaphorin 6D regulates the late phase of CD4+ T cell primary immune responses. Proceedings of the National Academy of Sciences of the United States of America. 2008; 105 (35):13015-13020 - 83.
Saradna A, Do DC, Kumar S, Fu QL, Gao P. Macrophage polarization and allergic asthma. Translational Research. 2018; 191 :1-14 - 84.
Kang S, Nakanishi Y, Kioi Y, Okuzaki D, Kimura T, Takamatsu H, et al. Semaphorin 6D reverse signaling controls macrophage lipid metabolism and anti-inflammatory polarization. Nature Immunology. 2018; 19 (6):561-570 - 85.
Yamada A, Kubo K, Takeshita T, Harashima N, Kawano K, Mine T, et al. Molecular cloning of a glycosylphosphatidylinositol-anchored molecule CDw108. Journal of Immunology. 1999; 162 (7):4094-4100 - 86.
Mine T, Harada K, Matsumoto T, Yamana H, Shirouzu K, Itoh K, et al. CDw108 expression during T-cell development. Tissue Antigens. 2000; 55 (5):429-436 - 87.
Liu H, Juo ZS, Shim AH, Focia PJ, Chen X, Garcia KC, et al. Structural basis of semaphorin-plexin recognition and viral mimicry from Sema7A and A39R complexes with PlexinC1. Cell. 2010; 142 (5):749-761 - 88.
Czopik AK, Bynoe MS, Palm N, Raine CS, Medzhitov R. Semaphorin 7A is a negative regulator of T cell responses. Immunity. 2006; 24 :591-600 - 89.
Esnault S, Kelly EA, Johansson MW, Liu LY, Han ST, Akhtar M, et al. Semaphorin 7A is expressed on airway eosinophils and upregulated by IL-5 family cytokines. Clinical Immunology. 2014; 150 (1):90-100 - 90.
Mizutani N, Nabe T, Yoshino S. Semaphorin 7A plays a critical role in IgE-mediated airway inflammation in mice. European Journal of Pharmacology. 2015; 764 :149-156