Although the TH2 effector response can coordinate the direct killing of some worms by enhancing innate effector cell functions, a major focus of the antihelminth response is expelling the worms and limiting the tissue damage they cause when they invade the host—functions that are both mediated by type 2 cytokines. IL-13 directly enhances the production of mucus by goblet cells, activates smooth muscle cells in mucosal tissues for hypermotility, and increases the migration and turnover of epithelial cells in the mucosa (see Fig. 11.15, first panel). In the intestines, which are the most common site of worm infestation, each of these actions is a critical component of the host response, as it helps to eliminate parasites that have attached to the epithelium and decreases the surface area available for colonization.
The response to helminths generates high levels of IgE antibody, induced by IL-4-producing TFH cells that develop in concert with TH2 cells (see Section 9-20). IgE binds to Fcεreceptors expressed by mast cells, eosinophils, and basophils, which arms them for antigen-specific recognition and activation. Type 2 adaptive responses also promote production of IgG1, which is recognized by macrophages and engages them in the type 2 response. IL-4 and IL-13 produced by TH2 cells also result in the differentiation of alternatively activated macrophages (also called M2 macrophages). Unlike classically activated, M1 macrophages, which differentiate after interaction with TH1 cells and are potent activators of inflammation (see Fig. 11.10), M2 macrophages participate in worm killing and expulsion, and also promote tissue remodeling and repair (see Fig. 11.15). A major difference between M1 and M2 macrophages is their different metabolism of arginine to produce antipathogen products. Whereas M1 macrophages express iNOS, which produces the potent intracellular microbicide nitric oxide (NO) (see Section 3-2), M2 macrophages express arginase-1, which produces ornithine and proline from arginine. Along with other factors, ornithine increases the contractility of mucosal smooth muscle and promotes tissue remodeling and repair (see Fig. 11.15). Through a mechanism that is unclear, ornithine has also been found to be directly toxic to IgG-coated larvae of certain helminths. Because helminths that have invaded tissues are too large to be ingested by macrophages, the targeted release of toxic mediators directly onto the worm by antibody-dependent cell-mediated cytotoxicity (ADCC) enables macrophages, as well as eosinophils (see below), to attack these large extracellular pathogens.
Macrophages activated by TH2 cells also appear to be important in walling off invading worms, as well as repairing tissue damage caused as worms migrate through host tissues. These ‘tissue repair’ functions of M2 macrophages are dependent on secreted factors important in tissue remodeling and include the stimulation of collagen production, formation of which requires proline that is generated by arginase-1 activity. Moreover, TH2-activated macrophages can also induce the formation of granulomas that entrap worm larvae in tissues. In this regard, antigen-specific macrophage activation by TH2 cells has non-redundant function in type 2 responses. Although ILC2 cells, and innate effector cells, may promote M2 macrophage activation via IL-13, they are unable to sustain this response. Thus, in several models of worm infection, antihelminth responses are considerably impaired in RAG-deficient or T-cell-depleted mice, demonstrating that sustained alternative activation of macrophages requires TH2 cells.