Decoy Receptors in the Regulation of T Helper Cell Type 2 Responses

Th2-driven responses are instrumental in disease processes including allergies, asthma, and helminth infection, and are characterized by the production of the cytokines IL-4, IL-5, IL-9, and IL-13. These cytokines form a complex network of molecular and cellular interactions that mediate protective immunity not only to worm infection, but also to induce inappropriate inflammatory responses to allergic challenge. Given the clinical importance of these molecules, considerable effort has gone into attempting to identify the relative contributions of the major Th2 cyto-kines to such disease processes. It has become apparent that Th2 responses are highly complex and might be regulated at many levels through a multitude of pathways, including temporal and spatial regulation of both cytokine and cyto-kine receptor transcription and translation, so as to initiate an appropriate defense mechanism as well as return to a basal level once the infection has been controlled. Thus, during an immune response certain signals lead to the up-regulation of cytokine secretion by specific cells whereas others lead to the expression of the cognate receptors of these ligands by responding cells, resulting in cellular activation where ligand and receptor expression coincide. However, this model is complicated by the existence of multiple cytokine receptors with overlapping binding spec-ificities. It is important, therefore, not only to determine the roles of the individual cytokines, but also the functions mediated by their receptors. IL-13 has proven to be an extremely important immu-noregulator and its direct roles in the generation of disease pathology has triggered the search for therapeutics capable of blocking the actions of IL-13 in vivo. Recent investigations have addressed the functional biology of IL-13 using in vivo models with defined Th2 responses. Complementary studies using IL-13 antagonists and IL-13–deficient mice have demonstrated that ablating IL-13 activity profoundly inhibits the pathophysiology of asthma (1–3) and impairs the expulsion of parasitic gastrointestinal helminths (4, 5). Similarly, overexpression of IL-13 in transgenic mice has highlighted the potentially detrimental responses initiated by this cytokine. As overexpression of IL-13 in mice leads to a broad disease phenotype it is important that in normal mice, and presumably in man, the levels of IL-13 are tightly controlled. The complexity of receptor usage and the potential diversity of signaling pathways combine with the temporal and spatial expression of the individual ligands to create a diversity of possible responses. The receptor components that interact with IL-13 are members of the haematopoi-etin receptor family and display the complexity …