The IL-5 produced by TH2 cells and ILC2 cells recruits and activates eosinophils (see Fig. 11.15), which have direct toxic effects on worms by releasing cytotoxic molecules stored in their secretory granules, such as major basic protein (MBP). In addition to Fcε receptors that arm them for degranulation with IgE, eosinophils bear Fc receptors for IgG and can mediate ADCC against IgGcoated parasites (see Fig. 10.38). They also express the Fcα receptor (CD89) and degranulate in response to stimulation by secretory IgA.
IL-3 and IL-9 produced by TH2 cells in the mucosae recruit, expand, and activate a specialized population of mast cells known as mucosal mast cells (see Fig. 11.15). The innate cytokines IL-25 and IL-33 also activate mucosal mast cells early in a response to helminths. Mucosal mast cells differ from their counterparts in other tissues by having only small numbers of IgE receptors and producing very little histamine. When activated by cytokines, or by the binding of worm antigens to receptor-bound IgE, mucosal mast cells release large amounts of preformed inflammatory mediators that are stored in secretory granules: prostaglandins, leukotrienes, and several proteases, including the mucosal mast cell protease (MMCP-1), which can degrade the epithelial tight junctions to increase permeability and fluid flow into the mucosal lumen. Together, the mast-cell-derived mediators increase vascular and epithelial permeability, increase intestinal motility, stimulate the production of mucus by goblet cells, and induce leukocyte recruitment, all of which contribute to the ‘weep and sweep’ response that helps to expel parasites from the host.
11-10 TH17 cells coordinate type 3 responses to enhance the clearance of extracellular bacteria and fungi.
The subset of effector T cells generated in response to infection by extracellular bacteria and fungi is TH17. At homeostasis, TH17 cells are deployed almost exclusively in the intestinal mucosa, where they contribute to the mutualistic relationship between the host and the intestinal microbiota—which is composed of extracellular bacteria and some fungi. However, they are also critical for defense against pathogenic extracellular bacteria and fungi that invade at barrier sites, as well as components of the normal microbiota that may enter the host when epithelial barrier function is compromised, whether as the result of trauma or pathogenic infection. In these settings, a principal function of TH17 cells is the orchestration of type 3 responses, in which neutrophils are the principal type of innate effector cell.
As discussed in Chapter 9, the development of TH17 cells is induced by the combined actions of TGF-β and the pro-inflammatory cytokines IL-6, IL-1, and IL-23 (see Fig. 9.31). The latter is preferentially produced by CD103+CD11b+ conventional dendritic cells that recognize MAMPs produced by extracellular bacteria, such as flagellin, which is recognized by TLR5; or MAMPs produced by fungi, such as β-glucan polymers of glucose expressed by yeast and fungi that are recognized by Dectin-1. As for TH1 and TH2 cells, the egress of TH17 cells from secondary lymphoid tissues is associated with altered chemokine expression: primarily the induction of CCR6, the ligand for which (CCL20) is produced by activated epithelial cells in mucosal tissues and skin, as well as TH17 cells themselves and ILC3 cells (see Figs. 11.8 and 11.9).