IL-4 and IL-13 Receptors
The IL-4 and IL-13 receptor subunits were among the first cytokine receptor systems described in the 1980s enabling the discovery of cytokine cell signaling, receptor subunit formation and cytokine regulation of immune responses. The IL-4R complex has been shown to be central in regulating type II-mediated immunity and inflammation toward extracellular parasitic infections, regulation of B-cell antibody isotype class switching and affinity maturation, and the progression of allergy, asthma, and atopic dermatitis in susceptible individuals. Many studies over the last 20 years have revealed the role of IL-4/IL-13R in the development of CD4+ T helper-mediated type 2 immunity and allergy. A new class of immune cells termed innate lymphoid cells (ILC), which express principally IL-13 (and IL-4 in certain circumstances), has recently been discovered. However, the exact roles of these cells and cytokines they secrete in orchestrating the development of both innate inflammatory and adaptive immunity remains to be fully elucidated. Recent studies have identified that IL-13R signaling via the different receptor molecules, IL-13 receptor α1 (IL-13Rα1) or IL-13Rα2 can have vastly different effects in regulating the balance of Th1- and Th2-mediated immunity. Dysfunction of these receptors has shown to cause many disease conditions such as allergy asthma, inflammation, atopic dermatitis, cancer, and neurodegenerative diseases.
IL-4 and IL-13 Receptor Complex
Cytokine IL-13 signals via two receptor systems; type II IL-4 receptor complex and also the poorly defined IL-13Rα2. IL-13 binds to IL-13Rα1 (65–70 kDa glycosylated protein) with modest affinity (KD = 30 nM), leading to recruitment of the IL-4Rα subunit and the activation of JAK/STAT6 signaling pathway (Fig. 1). In contrast, IL-13Rα2 (~65 kDa) has a short intracellular domain, binds to IL-13 with very high affinity (<10−15 M) under low IL-13 concentrations, and is thought to signal via a partially characterized mechanism resulting in TGF-β secretion (Fig. 1). IL-13Rα2 exists as two isoforms in mice, the membrane bound and the soluble forms. Interestingly, the latter form, which sequesters IL-13 in the cell milieu, is found in high concentrations in mouse urine. However, unlike in mice, human IL-13Rα2 only exists as a functional membrane bound receptor. It is postulated that IL-13 signaling via IL-13Rα1 complex can also activate alternative STAT3 signaling pathway (Cheng et al. 2012) (Fig. 2). However, under these circumstances whether IL-13Rα1 interacts with IL-4Rα, IL-13Rα2 or another receptor(s) are still debated.
Several notions have been put forward to explain how the type I and type II IL-4 receptors, preferentially respond to IL-4 or IL-13 to induce diverse immune functions, notably, (i) different binding affinities of the cytokines to type I and type II receptors, (ii) relative abundance of the receptor subunits and signaling molecules (i.e., JAKs) in the cell milieu, (iii) binding stability of the receptor complexes, and (iv) level of phosphorylation of the signaling molecules (i.e., tyrosine) associated with the different receptors, are among a few concepts.
Role of IL-4 and IL-13 Receptors in Infection and Vaccination
IL-4, IL-13, and their cognate receptors are potent mediators of the type 2 immunity and inflammatory processes, while also being inhibitory toward type 1 immunity and inflammation mediated by cytokines IFN-γ, IL-12, and IL-18. The commonly accepted roles of the IL-4/IL-13 receptor complex can be defined as (i) regulation of T helper 2 (Th2) cell development, (ii) M2 macrophage polarization, (iii) T follicular helper cell (Tfh)-dependent B cell and plasma cell differentiation, and (iv) antibody IgG1 and IgE isotype class switching.
IL-4 and IL-13 receptors are essential for inducing polarized type 2 immunity required for expulsion of extracellular parasitic infections. It is now established that group 2 innate lymphoid cells (ILC2) are the major source of both IL-13 and IL-4 early during infection required for the differentiation of Th2 immunity toward extracellular parasites. IL-13 expressed by ILC2 results in IL-13R signaling crucial for attraction, stimulation, and migration of dendritic cells to draining lymph nodes, while inducing a particular subset of dendritic cells (CD11b+ CD103-) to express the chemokine CCL17, required for stimulation of memory Th2 responses (Halim et al. 2016). The Th2 response includes the specialized CD4+ Tfh cells expressing IL-4, which induces B-cell STAT6-mediated antibody isotype class switching to IgG1 and IgE. Binding of an antigen to pathogen-specific IgE bound to FcεRI on mast cells and basophils induces degranulation and release inflammatory mediators, including histamines, proteases, chemotactic factors, cytokines TNF, IL-4, IL-5, IL-6, IL-1β, and IL-13, and metabolites that facilitate vasculature permeability, smooth muscle contraction, and mucous release by goblet cells and inflammatory cell activation resulting in the expulsion of mucosal parasites.
Activation of either the IL-4R type I (IL-4Rα/IL-2RγC, IL-4 only, hematopoietic cells) or type II (IL-4Rα/IL-13α, IL-4 or IL-13, most cell types) stimulates STAT6 cell signaling. While IL-4Rα and IL-13Rα1 are constitutively expressed, STAT6 activation also enhances transcription of IL-13Rα2 (David et al. 2001). IL-4Rα and IL-13Rα1 proteins are readily expressed on the cell surface, while IL-13Rα2 is primarily stored as an intracellular protein and upon activation appears on the cell surface (Daines and Hershey 2002). Under type 2 polarized conditions enhanced IL-4 and IL-13 expression activate type I IL-4 and II IL-4 receptors on cell surfaces, stimulating STAT6 signaling, which further potentiate Th2 immunity.
However, stimulation with cytokines IFN-γ, TNFα alone or in synergy with IL-17A (Fichtner-Feigl et al. 2006; Badalyan et al. 2014) rapidly induces surface expression of the transmembrane IL-13Rα2. IL-13Rα2 binds IL-13 with high affinity, compared to lower affinity IL-13Rα1 (Lupardus et al. 2010). IL-13Rα2 binding for IL-13 quickly outcompetes binding to IL-13Rα1, restricting STAT6 signaling. It is also known that cell surface expression of IL-13Rα2 promotes interaction between the intracellular domains of IL-13Rα2 and IL-4Rα and prevents IL-4Rα/IL-13Rα1 STAT6 signaling (Andrews et al. 2013). IL-13Rα2 activation by IL-13 or chitinase 3-like 1 (He et al. 2013) can stimulate monocyte-macrophage lineage cells to express TGF-β1 regulating inflammation, tissue remodeling and fibrosis following infection. IL-13 can therefore (i) stimulate the classic IL-4Rα/IL-13Rα1 complex activating STAT6 pathway-promoting Th2 immunity and (ii) in the presence of type 1 cytokines inhibit STAT6 signaling by activating IL-13Rα2 potentiating alternative Th1 or Th17 responses, demonstrating a dual role in infection and immunity.
Infection with viruses usually generates polarized type 1 immunity mediated by cytokines IFN-γ and IL-12. However, respiratory virus infection, such as influenza virus can induce expression of IL-13 by lung ILC2 exacerbating allergy/asthma responses (Duerr et al. 2016), temporally diverting the type 1 antiviral responses favoring viral replication. IL-13 and to a lesser extent IL-4 are also detrimental to the development of type 1 immune-mediated antiviral vaccine responses (Ranasinghe and Ramshaw 2009; Ranasinghe et al. 2007). In animal studies we have shown that inhibition of IL-13 signaling by sequestering IL-13 using a decoy receptor (Ranasinghe et al. 2013) or by blocking the IL-4/IL-13R complex using an IL-4Rα antagonist (Jackson et al. 2014) co-expressed by a heterologous poxvirus – human immunodeficiency virus (HIV) intranasal/intramuscular prime-boost vaccine strategy – can induce enhanced high-quality antiviral mucosal and systemic CD8 T-cell responses with greater cell-mediated protective efficacy to mucosal viral challenge. The transient inhibition of IL-4R and/or IL-13R signaling at the priming vaccination site was shown to induce enhanced recruitment of unique dendritic cells (CD11b+ CD103-), associated with the resulting high-quality antiviral T-cell immunity (Trivedi et al. 2014). Interestingly, sequestering IL-13 during vaccination resulted in the loss of vaccine-induced IgG2a antibody isotype expression (Jackson et al. 2014), while transient inhibition of type I and type II IL-4Rα (using IL-4R antagonist), which prevented both IL-4/IL-13 signaling via STAT6 pathway promoted IgG2a antibody isotype switching. Further investigation revealed that level of IL-13 at the vaccination site could significantly regulate IgG2a expression independently of STAT6 involvement (Hamid et al., in review). These observations highlight the importance of the numerous, and still to be fully defined, immune regulatory roles of IL-4Rα and IL-13R subunits in determining the balance of T- and B-cell immunity following infection and/or vaccination.
IL-4/IL-13 Receptor Regulation Following Infection and/or Vaccination
Role of IL4 and IL-13 Receptors in Allergy and Asthma
IL-4 and IL-13 are major players in allergy and asthma. During allergic asthma, IL-4 (i) can activate Fc receptors to promote degranulation and release of inflammatory mediators and also (ii) bind to type I and type II IL-4Rα complexes to enhance alternatively activated macrophage (AAM) genes to promote Th2 responses. On the other hand, IL-13 can bind to type II IL-4Rα receptor complex and induce allergic effector functions such as airway hypersensitivity, mucous and collagen production, and lung fibrosis. Additionally, IL-4 signaling via STAT6 pathway can also suppress immune regulation and ultimately leads to immune overeactivity. IL-17 is also associated with increased asthma severity and pathogenesis. Interestingly, IL-13 can also bind to IL-13Rα1 expressed on TH17 cells, promote STAT6 signaling, and reduce IL-17 expression, hence negatively regulating the allergic asthma response (Newcomb et al. 2009).
Therapeutic Potential of IL-4 and IL-13 Receptors
Studies indicate that modulating the IL-4/IL-13 receptors could be used as therapeutic or vaccine targets to treat conditions associated with dysfunction of IL-4 and IL-13. IL-4R antagonists, soluble IL-13Rα1, and monoclonal antibodies to block the different IL-4/ IL-13 receptor subunits have been tested as therapeutic agents to prevent asthma/allergy including atopic dermatitis. Overexpression of IL-13Rα2 has been associated with tumors and cancers. Thus, anticancer therapies and vaccines that target IL-13Ra2α2 are also been evaluated. Additionally, in the context of improving vaccine-specific immunity, IL-4Rα antagonist adjuvant vaccines (which can bind to type I and type II IL-4Rα complexes and transiently block STAT6 signaling); and IL-13Rα2 adjuvant vaccines (which can transiently sequester IL-13 at the vaccination site) have shown promising protective outcomes in animal models. Thus, these novel vaccine approaches offer good optimism for the future.
While the activity of the classic IL-4Rα, IL-13Rα1 STAT6 activation is well understood for the progression of allergy/asthma or immunity toward extracellular parasites, little is known in the context of the complex cytokine interplay with other immune/inflammatory conditions (e.g., psoriasis), or even the normal circumstance of developing immunity toward viral or bacterial infections involving IFNγ or IL-17A. Suboptimal outcomes of many current clinical vaccine trials also suggest that innovative approaches are urgently needed to combat chronic pathogens such as (HIV, tuberculosis, malaria) that evade the host immune system. Our studies have shown that selectively blocking IL-4 and or IL-13R signaling can significantly improve T-cell vaccine efficacy and B-cell immunity by activating desirable dendritic cell subsets at the vaccination site. We have shown that ILC are the major source of IL-13 at the vaccination site, and the level of IL-13 can significantly modulate antigen presenting cell recruitment, which can affect the quality of adaptive immunity. Therefore, a greater understanding of how the IL-4/IL-13 receptor complexes are involved in the regulation of innate and adaptive immune cells (ILC, antigen presenting cells, T- and B-cell subsets) is urgently needed, which will enable the development of powerful and efficacious prophylactic and therapeutic mucosal/systemic vaccine strategies against chronic pathogens. These developments could also eventually lead to treatments for other chronic inflammatory conditions (such as inflammatory bowel disease (IBD)) by regulating the balance between stimulatory and suppressive cytokine signaling.
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