ILCs function in innate immunity as effector cells that amplify the signals delivered by innate recognition. They are stimulated by cytokines produced by other innate cells, such as macrophages or dendritic cells, that have been activated by innate sensors of microbial infection or cellular damage. Three major subgroups of ILCs are defined, largely on the basis of the types of cytokines that each produces. Group 1 ILCs (ILC1s) generate IFN-γ in response to activation by certain cytokines, in particular IL-12 and IL-18, made by dendritic cells and macrophages, and they function in protection against infection by viruses or intracellular pathogens. NK cells are now considered to be a type of ILC. ILC1s and NK cells are closely related, but have distinct functional properties and differ in the factors required for their development. NK cells are more similar to CD8 T cells in function, while ILC1s resemble more closely the TH1 subset of CD4 T cells (see Section 3-24). NK cells can be distinguished from recently identified ILC1 cells in several ways. NK cells can be found within tissues, but they also circulate through the blood, while ILC1 cells appear to be largely non-circulating tissue-resident cells. In the mouse, conventional NK cells express the integrin α2 (CD49b), while ILC1 cells, for example in the liver, lack CD49b but express the surface protein Ly49a. Both NK and ILC1 cells require the transcription factor Id2 for their development, but NK cells require the cytokine IL-15 and the transcription factors Nfil3 and eomesodermin, while liver ILC1 cells require the cytokine IL-7 and the transcription factor Tbet.
ILC2s produce the cytokines IL-4, IL-5, and IL-13, in response to various cytokines, particularly thymic stromal lymphopoietin (TSLP) and IL-33. ILC2 cytokines function in promoting mucosal and barrier immunity and aid in protection against parasites. ILC3s respond to the cytokines IL-1β and IL-23 and produce several cytokines, including IL-17 and IL-22, which increase defenses against extracellular bacteria and fungi. IL-17 functions by stimulating the production of chemokines that recruit neutrophils, while IL-22 acts directly on epithelial cells to stimulate the production of antimicrobial peptides such as RegIIIγ (see Section 2-4).
The classification of ILC subtypes and the analysis of their development and function is still an active area, and studies to define the relative importance of these cells in immune responses are ongoing. The ILC subgroups identified so far appear to be highly parallel in structure to the subsets of effector CD8 and CD4 T cells that were defined over the last three decades. The transcription factors that control the development of different ILC subsets seem, for now at least, to be the same as those that control the corresponding T-cell subsets. Because of these similarities, we will postpone a detailed description of ILC development until Chapter 9, where we will cover this topic along with the development of T-cell subsets.
3-24 NK cells are activated by type I interferon and macrophage-derived cytokines.