It appears that each of the three major ILC and effector CD4 T-cell subsets (ILC1/ILC2/ILC3 and TH1/TH2/TH17, respectively) evolved to enhance and coordinate the functions of, and integrate adaptive immunity with, different arms of the myelomonocytic pathway for optimal eradication of different classes of pathogens: monocyte and macrophages are enhanced by TH1 cells; eosinophils, basophils, and mast cells by TH2 cells; and neutrophils by TH17 cells. The three major types of immune responses are controlled by cytokine and chemokine networks, as discussed below.
Fig. 11.5 Integration of ILCs, T-cell subsets, and innate effector cells into immune effector modules. The major inductive and effector cytokines, and transcription factors (e.g., ID2, T-bet, GATA3, RORγt, and AHR), that are associated with each effector module are shown. See text for details.
Type 1 responses are characterized by the actions of group 1 ILCs (ILC1), TH1 cells, opsonizing IgG isotypes (for example, IgG1 and IgG2), and macrophages in response to intracellular pathogens, including intracellular bacteria, viruses, and parasites (see Fig. 11.5). Type 2 responses are characterized by the actions of group 2 ILCs (ILC2), TH2 cells, IgE, and the innate effector cells eosinophils, basophils, and tissue mast cells, the latter two of which are armed for function by IgE bound to surface Fcε receptors. Type 2 responses are induced by, and target, multicellular parasites, or helminths. Type 3 responses are characterized by the actions of group 3 ILCs (ILC3), TH17 cells, opsonizing IgG isotypes, and neutrophils in response to extracellular bacteria and fungi. It is the activation of different subsets of ILCs early in the innate response that sets the stage for polarized type 1, type 2, or type 3 responses. Unlike the effector CD4 T cells with which they share overlapping functional features, ILCs do not require priming and differentiation in order to acquire their effector functions; hence they are able to respond rapidly to amplify the activities of resident and recruited innate effector cells. Here we will consider in more detail the induction and actions of ILC subsets, as these responses precede and are integrated with adaptive T-cell responses.
As discussed in Chapter 3, ILC1s and related NK cells are characterized by their production of IFN-γ in response to IL-12 and IL-18 produced by pathogen-activated dendritic cells and macrophages. Functionally, ILC1s and NK cells most closely resemble TH1 cells and CTLs, respectively. ILC1s lack the cytolytic granules that are characteristic of NK cells and CTLs, and appear to promote clearance of intracellular pathogens through their activation of infected macrophages by the release of IFN-γ. Thus, through their production of IL-12 and IL-18, macrophages can rapidly induce ILC1 production of IFN-γ, which acts back on the macrophage to induce its heightened killing of intracellular pathogens several days prior to the development and recruitment of TH1 cells. Moreover, the production of IFN-γ by ILC1s may contribute to the early polarization of TH1 cells, linking the effector function of these cells to the induction of the TH1 cell response that follows. Similarly, the rapid induction of the cytolytic activity of NK cells enables the killing of a range of pathogen-infected cells, through the recognition of surface molecules that are expressed on the target cells (see Section 3-23), in advance of the antigen-driven development and deployment of cytolytic CD8 T cells. Also, similar to the effect on TH1 cells of IFN-γ production by ILC1s, the production of IFN-γ by activated NK cells may contribute to the enhanced differentiation of cytolytic CD8 T cells.