ILC2s that reside in mucosal tissues are preferentially activated by the cytokines thymic stromal lymphopoietin (TSLP), a STAT5-activating cytokine, and IL-33 or IL-25, each of which are produced in response to helminths. These cytokines are primarily produced by epithelial cells that sense molecular patterns common to helminths, such as chitin, a polysaccharide polymer of β-1,4-N-acetylglucosamine that is a widespread constituent of helminths, the exoskeletons of insects, and some fungi. Activated ILC2s rapidly produce large amounts of IL-13 and IL-5; IL-13 stimulates mucus production by goblet cells in the epithelium and mucosal smooth muscle contractions that facilitate worm expulsion; and IL-5 stimulates the production and activation of eosinophils that can kill worms. Unlike TH2 cells, with which they share functional features, ILC2s appear to produce little or no IL-4 in vivo, suggesting that they might not directly promote TH2 differentiation. However, eosinophils and basophils that are recruited by chemokines produced by ILC2s are activated to produce IL-4 in response to the IL-5 and IL-13 produced by ILC2s, possibly providing an indirect mechanism by which TH2 differentiation is directed by ILC2s. Moreover, IL-13 produced by ILC2s appears to regulate the activation and migration to regional lymphoid tissues of dendritic cells that promote TH2 differentiation, although it is unclear whether these dendritic cells can also produce IL-4.
ILC3s play a critical early role in defense against extracellular bacteria and fungi at barrier tissues. Similarly toTH17 cells, ILC3s are responsive to IL-23 and IL-1β; these cytokines elicit the production of IL-17 and IL-22, which promote early type 3 responses. IL-17 is a pro-inflammatory cytokine that acts on a variety of cells, including stromal cells, epithelial cells, and myeloid cells, to stimulate the production of other pro-inflammatory cytokines (for example, IL-6 and IL-1β), hematopoietic growth factors (G-CSF and GM-CSF), and chemokines that recruit neutrophils and monocytes. IL-22 acts on epithelial cells to induce their production of antimicrobial peptides (AMPs) and promote enhanced barrier integrity. As with other ILCs, the cytokines produced by ILC3s act indirectly via IL-6 and IL-1β in a positive feedback loop to enhance type 3 responses by increasing local production of IL-23 and IL-1β. Through induction of elevated IL-6, IL-1β, and IL-23, ILC3s may also promote the differentiation of TH17 cells in mucosal lymphoid tissues, where they can be found in substantial numbers.
In a further parallel with effector CD4 T cells, an important feature of ILCs is that they ‘license’ other innate immune cells for killing or expulsion of microbes, but they do not do so themselves. Instead, myelomonocytic cells, and even cells of the mucosal epithelium, are the agents of ILCs and effector CD4 T cells; they are recruited and/or activated through the pro-inflammatory cytokines and chemokines that these lymphoid cells produce. An exception is NK cells, which, like effector CD8 T cells, directly kill target cells that harbor intracellular pathogens. As we will discuss below, because of their ability to focus effector cytokines on antigen-bearing target cells and to induce B-cell maturation and the production of class-switched antibodies, effector CD4 T cells provide an additional layer of licensing of innate effector cells that increases their lethality and ability to achieve microbial clearance.
Summary.