Spatial regulation of IL-4 signalling in vivo

•During a Th2 response, IL-4 dominates in the lymph node while IL-13 operates in the infected tissue.•Within the lymph node, IL-4 production is restricted to CD4+ T cells in the B cell follicle.•Despite restricted production, IL-4 signalling occurs throughout the Th2 lymph node.•Widespread IL-4 signalling affects bystander cells and alters their subsequent response to antigen.•Cytokine conditioning of bystander cells may compromise protective immunity during co-infection. Type 2 immune responses are defined by the cytokines interleukin 4 (IL-4), IL-5 and IL-13 and the cellular and physiological changes that these cytokines induce, including IgE production, eosinophilia, mast cell degranulation, mucus secretion and smooth muscle contraction. Together these responses provide a “weep and sweep” reflex that is optimised to expel parasitic worms. The same response can also be pathological when mis-timed or activated inappropriately. Current understanding of the orchestration and regulation of type 2 immunity is rapidly advancing, with recent identification of participating innate cells and elucidation of the cytokine signals responsible for their activation. In vivo, the outcome of cytokine signalling is critically dependent on timing, location and context. In this commentary, we describe the spatiotemporal control of type 2 cytokine signalling, consider its implications for bystander cells, and discuss its significance during co-infection.