Diversity and dialogue in immunity to helminths

Key Points Infection with large metazoan parasites (helminths) typically induces a type 2 immune response. Redundancy within the immune system, as well as extensive dialogue between cells of the immune system and non-immune cells, generates enormous complexity. The central player in type 2 immunity is the CD4 + T helper 2 (T H 2) cell, which produces a broad range of cytokines, including interleukin-4 (IL-4) and IL-13, which act on target cells expressing the IL-4 receptor α-chain. Target cells include most cells of the immune system but also local tissue cells such as epithelial cells that line mucosal surfaces. Cells of the innate immune system, such as the recently described 'innate helper cells', can also produce type 2 cytokines. These cells function as effectors during the early stages of infection, but additionally create an environment that favours the induction of T H 2-type responses. T H 2-type responses are initiated by alarm signals from epithelial cells, as well as by specific recognition of helminth products. A strict requirement for dendritic cells in this process has been established. In addition to killing or expelling helminth parasites, type 2 immune responses contribute to rapid tissue repair, and this sometimes leads to fibrosis-related pathology. Many facets of type 2 immunity are consistent with evolutionary origins in wound-healing pathways, a reflection of the capacity of helminth parasites to damage tissue through migration and feeding. T cell dynamics change over time, and T H 2-type responses often decline during chronic helminth infection. Regulatory pathways, including regulatory T cells, restrain pathology and immune responses during infection, and some helminths are able to actively induce the expansion of regulatory populations. Because mammals evolved in the presence of chronic infection, their immune systems may have compensated for the immune dampening effects of helminths. If so, over-reactive responses to innocuous antigens in the absence of infection may contribute to autoimmune disease and allergy. Exciting new studies have uncovered many of the molecules and cell types that contribute to 'type 2' immune responses. Here, Judith Allen and Rick Maizels discuss how these responses are generated and provide protective immunity during helminth infection. The vertebrate immune system has evolved in concert with a broad range of infectious agents, including ubiquitous helminth (worm) parasites. The constant pressure of hel