Type 2 immunity is directed against parasitic helminths: roundworms (nematodes) and two types of flatworms—tapeworms (cestodes) and flukes (trematodes). Unlike microbial pathogens, or ‘micropathogens’ (bacteria, viruses, fungi, and protozoa), which replicate rapidly and can overwhelm host defenses by sheer numbers, most helminths do not replicate in their mammalian host. Moreover, helminths are multicellular; they are metazoan ‘macropathogens’ that are far too large—ranging in size from approximately 1 mm to over 1 meter—to be engulfed by host phagocytic cells, and therefore require very different strategies for host defense. In the developing world, the intestines of virtually all animals and humans are colonized by helminth parasites (Fig. 11.14). Many of these infections may be cleared rapidly by the generation of an effective type 2 response, although often the host response is successful in reducing worm burden, but not in completely clearing the parasite, resulting in chronic disease. In these circumstances, the parasite persists for long periods despite the host’s attempts to expel it, and causes disease by competing with the host for nutrients, or by causing local tissue injury.
Irrespective of the type of helminth involved, or its site of host entry, the host adaptive response is orchestrated by TH2 cells (Fig. 11.15; see also Fig. 9.30). The TH2 response is induced by the actions of worm products on a variety of different innate cells: epithelial cells, ILC2 cells, mast cells, and dendritic cells. Dendritic cells required for the presentation of helminth antigens to naive CD4 T cells appear to be activated by IL-13 produced by ILC2 cells and innate cytokines, such as epithelium-derived TSLP, which repress the development of TH1and TH17-inducing dendritic cells in favor of dendritic cells that promote TH2 cell differentiation. The initial source of the IL-4 required for TH2 cell differentiation appears to be context-specific and redundant. Thus, although several cell types have been proposed as the source, including iNKT cells, mast cells, and basophils, none of these has been proven to be essential.
The development of TH2 cells in draining lymphoid tissues is followed by their exodus to sites of helminth invasion, where they enhance the recruitment and function of circulating type 2 innate effector cells—eosinophils, basophils, tissue mast cells, and macrophages. Like TH1 and TH17 cells, TH2 cells express a distinct complement of chemokine receptors that is shared with the circulating innate effector cells with which they interact, thus selectively guiding them to sites of ongoing type 2 responses (see Figs. 11.8 and 11.9). CCR3 and CCR4 are expressed both by TH2 cells and by eosinophils and basophils, as is CRTH2, the ligand for which is prostaglandin D2, a lipid mediator that is produced by activated tissue mast cells. Ligands for CCR3 (for example, the eotaxins CCL11, CCL24, and CCL26) are produced by multiple innate immune cells in tissue sites of helminth infection and are induced by IL-4 and IL-13 signaling. Hence, ILC2 cells, TH2 cells, and eosinophils and basophils can each amplify the recruitment of other type 2 cells through this chemokine network.