Th2 cells produce the cytokines IL-4, IL-5, and IL-13, which are involved in eradication of helminth infections and tissue repair after injury. Th2 reactions are also central to the development of allergic diseases.
Development of Th2 Cells
Th2 differentiation occurs in response to helminths and allergens and is induced by cytokines produced at sites of epithelial injury or stress (Fig. 1). Epithelial cells that are damaged by infections or environmental insults produce IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), all of which promote the development of Th2 cells and the activation of ILC2s. These cytokines have been called alarmins because they raise the alarm at sites of epithelial injury for immune responses to get activated. They are structurally distinct and trigger complex signaling pathways, some of which involve JAK-STAT molecules. They may activate T cells directly, but it is more likely that they endow DCs with the capacity to induce Th2 responses or activate ILC2s that promote Th2 differentiation. Because the alarmins are produced mainly by epithelial cells, Th2 responses tend to be prominent at epithelial barriers. Once Th2 cells have developed, they secrete IL-4, which promotes more Th2 responses.
Fig1. Differentiation of Th2 cells. Dendritic cells may respond to cytokines produced in epithelia by becoming Th2 inducers, by mechanisms that are not well defined. Interleukin-4 (IL-4) produced by activated T cells themselves or by mast cells and eosinophils, especially in response to helminths, activates the transcription factors GATA3 and STAT6, which stimulate the differentiation of naive CD4+ T cells to the Th2 subset. IL-4 produced by the Th2 cells amplifies this response and inhibits the development of Th1 and Th17 cells. TSLP, thymic stromal lymphopoietin.
IL-4 stimulates Th2 development by activating the transcription factor STAT6, which, together with TCR signals, induces expression of GATA3 (see Fig. 1). GATA3 is a transcription factor that is required for the expression of the Th2 cytokines IL-4, IL-5, and IL-13. GATA3 directly interacts with the promoters of these cytokine genes and also opens up the cytokine gene loci for accessibility to other transcription fac tors. This is similar to the way in which T-BET influences IFN-γ expression. GATA3 functions to stably commit differentiating cells toward the Th2 phenotype, enhancing its own expression through a positive feedback loop. Furthermore, GATA3 blocks Th1 differentiation by inhibiting expression of the signaling chain of the IL-12 receptor. Knockout mice lacking IL-4, STAT6, or GATA3 are deficient in Th2 responses.
Functions of Th2 Cells
The cytokines produced by Th2 (and related Tfh) cells stimulate IgE production, activate eosinophils and mast cells, which promote the elimination of helminths, and induce a type of activated macrophages that participate in tissue repair (Fig. 2). We will first describe the properties of these cytokines and then their roles in host defense.
Fig2. Functions of Th2 cells. CD4+ T cells that differentiate into Th2 cells secrete interleukin-4 (IL-4), IL-5, and IL-13. IL-4 (and IL-13) act on B cells to stimulate production of antibodies that bind to mast cells and eosinophils, such as immunoglobulin (Ig) E. Help for antibody production may be provided by T follicular helper (Tfh) cells that produce IL-4 and IL-13 and reside in lymphoid organs, and not by classical Th2 cells. IL-5 activates eosinophils, a response that is important for defense against helminthic infections. IL-4 and IL-13 induce an alternative pathway of macrophage activation and inhibit classical Th1-mediated macrophage activation. APC, Antigen-presenting cell.
Interleukin-4
IL-4 is the signature cytokine of the Th2 subset and functions as both an inducer and an effector cytokine of these cells. It is a member of the type I four–α-helical cytokine family. The principal cellular sources of IL-4 are CD4+ T lymphocytes of the Th2 subset, ILC2s, and activated mast cells. The IL-4 receptor consists of a cytokine-binding α chain that is a member of the type I cytokine receptor family, associated with the γc chain shared by other cytokine receptors. The IL-4 receptor signals by a JAK-STAT pathway involving JAK1, JAK3, and STAT6, and by a pathway that involves the insulin response substrate (IRS) protein called IRS2. Activated STAT6 induces transcription of genes that account for many of the actions of this cytokine. IL-4 and IL-13 receptors share one of their two chains (described later). IL-4 has important actions on several cell types.
• IL-4 (and IL-13) produced by Tfh cells stimulates B-cell Ig heavy-chain class switching to the IgE isotype. IgE is the principal mediator of immediate hypersensitivity (allergic) reactions, which involve IgE-mediated mast cell activation. IL-4 also enhances switching to IgG4 (in humans, or the homologous IgG1 in mice), but the significance of this role of IL-4 is unclear because these IgG subclasses do not bind to mast cell or phagocyte Fc receptors or activate complement.
• IL-4 stimulates the development of Th2 effector cells from naive CD4+ T cells. This function of IL-4 was described earlier.
• IL-4, together with IL-13, contributes to an alternative form of macrophage activation that is distinct from the macro phage response to IFN-γ. IL-4 and IL-13 suppress IFN-γ mediated classical macrophage activation and thus inhibit the defense against intracellular microbes that are destroyed by phagocytosis. The alternative macrophage activation pathway is described later.
• IL-4 (and IL-13) stimulates peristalsis in the gastrointestinal tract and IL-13 increases mucus secretion from airway and gut epithelial cells. Both actions contribute to elimination of helminths and possibly other microbes at epithelial surfaces.
• IL-4 and IL-13 stimulate the recruitment of leukocytes, notably eosinophils, by promoting the expression of adhesion molecules on endothelium and the secretion of chemokines that bind chemokine receptors expressed on eosinophils.
Interleukin-13
IL-13 is structurally and functionally similar to IL-4 and also plays a role in immunity against helminths and in allergic diseases. IL-13 is a member of the type I four–α-helical cytokine family. IL-13 is produced mainly by the Th2 subset, but group 2 ILCs and other leukocytes may also produce the cytokine. The IL-13 receptor is a heterodimer of the IL-4R α chain and the IL-13R α1 chain. This complex can bind both IL-4 and IL-13 with high affinity and also signals through a JAK1, JAK3, and STAT6 pathway. The receptor is expressed on a wide variety of cells, including B cells, mono nuclear phagocytes, DCs, eosinophils, basophils, fibroblasts, endothelial cells, and bronchial epithelial cells.
IL-13 works together with IL-4 in defense against helminths and in allergic inflammation. Some of the actions of IL-13 overlap with those of IL-4; others are distinct. Both IL-13 and IL-4 can activate B cells to switch to IgE and some IgG isotypes, enhance recruitment of leukocytes, and are involved in alternative macrophage activation. IL-13 stimulates mucus production by airway epithelial cells, an important component of allergic reactions, such as asthma. Unlike IL-4, IL-13 is not involved in Th2 differentiation.
Interleukin-5
IL-5 is an activator of eosinophils and serves as the principal link between T-cell activation and eosinophilic inflammation. It is a homodimer of a polypeptide containing a four–α-helical domain and is a member of the type I cytokine family. It is produced mainly by Th2 cells and ILC2s. The IL-5 receptor is a heterodimer composed of a unique α chain and a common β chain (βc), which is also part of the IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors. The major IL-5-induced signaling pathway involves JAK2 and STAT3.
The principal actions of IL-5 are to activate mature eosinophils and to stimulate the growth and differentiation of eosinophils. Activated eosinophils are able to kill helminths.
Roles of Th2 Cells in Host Defense
Th2 cells function in the defense against helminthic and other infections by several mechanisms (see Fig. 2).
• IgE- and eosinophil-mediated reactions. Helminths are too large to be phagocytosed by neutrophils and macrophages and may be more resistant to the microbicidal activities of these phagocytes than are most bacteria and viruses. Therefore, other mechanisms are needed to eradicate helminth infections. IL-4 and IL-13 stimulate the production of helminth-specific IgE antibodies, which may activate mast cells at the site of infection. IL-5 activates eosinophils, and these cells release their granule contents, including major basic protein and major cationic protein, which are capable of destroying the tough integuments of helminths (see Chapter 16). In allergic reactions, IgE coats mast cells and induces their degranulation upon encounter with antigen.
• Host defense at mucosal barriers. Cytokines produced by Th2 cells are involved in blocking entry and promoting expulsion of microbes from mucosal organs by stimulating mucus production and intestinal peristalsis. Thus, Th2 cells play an important role in host defense at the barriers with the external environment, sometimes called barrier immunity.
• Alternative macrophage activation and tissue repair. IL-4 and IL-13 activate macrophages to express enzymes that promote collagen synthesis and fibrosis. The macrophage response to Th2 cytokines has been called alternative macrophage activation (Fig. 3) to distinguish it from the activation induced by IFN-γ, which was characterized first (and hence the designation classical) and which results in potent microbicidal functions and inflammation. Alternatively activated (also called M2) macrophages produce IL-10 and transforming growth factor–β (TGF-β), cytokines that terminate inflammation and initiate repair after diverse types of tissue injury. These macrophages induce scar formation by secreting growth factors that stimulate fibroblast proliferation (platelet-derived growth factor), collagen synthesis (TGF-β), and new blood vessel formation or angiogenesis (fibroblast growth factor). The separation of classical and alternative macrophage activation provides a useful context for understanding different activation and functional states of macrophage, but there are no definitive markers for these populations and there is consider ably more phenotypic and functional heterogeneity among macrophages. Therefore, these macrophage populations are sometimes called M1-like and M2-like.
Fig3. Classical and alternative macrophage activation. Different stimuli activate tissue macrophages to develop into functionally distinct populations. Classically activated macrophages are induced by microbial products and cytokines, particularly interferon-γ (IFN-γ), and are microbicidal and promote inflammation. Alternatively activated macrophages are induced by interleukin-4 (IL-4) and IL-13 produced by Th2 cells and other leukocytes and function to control inflammation and to promote tissue repair and fibrosis. Some evidence suggests that M2 macrophages comprise subpopulations, some of which are mainly anti-inflammatory and others are responsible for tissue repair. NO, Nitric oxide; ROS, reactive oxygen species; TGF-β, transforming growth factor–β; TLR, toll-like receptor.
