Although multiple other cytokines can participate in type 2 immune responses, the signature cytokines associated with this immune program are IL-4, IL-5, IL-9 and IL-13. The genes for all four of these cytokines are found on the same chromosome in humans, and IL-4, IL-5 and IL-13 are found on the same chromosome in mice. The degree of homology between IL-4 and IL-13 suggests that they originated through a gene duplication event. Research from multiple groups has revealed that, while some of the functions of these cytokines can overlap, they each play important and nonredundant roles in type 2 immune responses. Transgenic overex
Fig. 1 Cytokines in inflammatory response.
IL-4 is often considered the hallmark cytokine of type 2 immunity. IL-4 can bind both the type I IL-4 receptor, which consists of the IL-4Rα chain paired with the common γ chain, and the type II IL-4/IL-13 receptor, which consists of the IL-4Rα chain paired with the IL-13Rα1 chain. In contrast, IL-13 does not bind the type I IL-4 receptor, but can bind the type II IL-4R or the decoy receptor IL-13Rα2, which is membrane-bound in humans and both membrane-bound and soluble in mice. Type I IL-4 receptor is mainly expressed on hematopoietic cells, while type II IL-4 receptor is expressed ubiquitously, including on nonhematopoietic cells. Binding of IL-4 to IL-4Rα leads to sequential activation of JAK-1 and STAT-6, which leads to the downstream effector functions of this cytokine. Binding of IL-4 to type I IL-4R is associated with promotion of Th2 differentiation and also the switching to IgE and IgG1 antibody isotypes by B cells. Binding of IL-4 or IL-13 to type II IL-4R mediates the tissue manifestations of allergic immunity including goblet cell hyperplasia and mucus secretion, smooth muscle contraction and the development of fibrosis. The actions of IL-4 and IL-13 and type II IL-4R signaling have also been associated with the promotion of macrophage alternative activation. However, it is important to note that differential affinities and binding patterns of IL-4 and IL-13 to the type II IL-4R are such that IL-13 is likely a more potent driver of type II IL-4R signaling. Indeed, despite utilization of the same receptor, multiple groups have demonstrated that IL-13 has multiple nonredundant functions during helminth infection and the development of allergic inflammation.
IL-5 is another cytokine associated with type 2 immune responses. IL-5 signals through a receptor comprised of IL-5Rα and common β chain subunits. Signaling through the IL-5Rα chain is associated with activation of JAK2, STAT-5 and multiple additional downstream signaling pathways. IL-5 is a growth factor for a specific subset of B cells called B1 cells, which have limited B cell receptor diversity and are major sources of IgM. IL-5 transgenic mice display a remarkable increase in the number of B1 cells, resulting in increased serum IgM, IgA and IgE, and IL-5-/-, and IL- 5Rα-/- mice have reduced numbers of B1 cells and half as many IgA-secreting cells in the intraepithelial lymphoid tissue of the intestine. IL-5 is also has multiple effects on eosinophils. IL-5 prolongs eosinophil survival by preventing eosinophil apoptosis, possesses eosinophil chemotactic activity, increases eosinophil adhesion to endothelial cells promoting migration, and also enhances eosinophil effector function. Consequently, IL-5-/- and IL-5Rα-/- also have reduced baseline eosinophil numbers, and the resulting eosinophils appear to be functionally impaired.
IL-9 production is also associated with type 2 immunity. IL-9 signals through a receptor composed of IL-9Rα and common γ chains, and signaling involves activation of JAK-1 and STAT-1, STAT-3 and STAT-5. IL-9 was first characterized as a T cell and mast cell growth factor. However, the role of this cytokine in promotion of T cell growth and function is controversial. IL-9-/- mice have reduced goblet cell hyperplasia and defects in mast cell recruitment in a pulmonary granuloma model. In contrast, IL-9-/- mice display normal levels of lung inflammation and airway hyperreactivity in a standard sensitization model, and have no observable defects in immunity to the helminth Nippostrongylus brasiliensis. Further studies are necessary to fully elucidate the role of IL-9 in type 2 immunity.
A multitude of recent studies have revealed new and important roles for the cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) in the initiation of type 2 immune responses. Although multiple cellular sources for each of these cytokines have been reported, the majority of studies have focused on their ex