Innate lymphoid cells (ILCs), which were introduced in Chapter 2, are bone marrow–derived cells with lymphocyte morphology that were discovered as cells that produced cytokines similar to those made by helper T cells but lacked TCRs. There are different subsets of ILCs that arise from the same common lymphoid precursor that gives rise to B and T cells, but the precise steps in ILC development are not fully understood, especially in humans. During their development, there are branch points that give rise to three different “helper” subsets of ILCs, which function mainly by secreting different types of cytokines, similar to CD4+ helper T-cell subsets, and a separate branch giving rise to NK cells, which function as cytotoxic effectors in addition to secreting the cytokine IFN- γ, similar to CD8+ CTLs. We will describe cytokine-producing ILC subsets in this section and NK cells in the following section.
Three subsets of ILCs, called ILC1, ILC2, and ILC3, produce different cytokines and express different transcription fac tors, analogous to the Th1, Th2, and Th17 subsets of CD4+ T lymphocytes (Fig. 1). ILC1s produce IFN-γ and express the transcription factor T-BET, like Th1 cells. ILC2s produce mainly IL-5 and IL-13 and express the transcription factor GATA3, like T h2 cells. ILC3s produce IL-22 and/or IL-17 and express the transcription factor RORγt, like Th17 cells. Because ILCs do not express T-cell receptors, they must be activated by different mechanisms than helper T cells to produce these cytokines. The best defined stimuli for cytokine production by ILCs are other cytokines that are released during innate responses to infections and tissue damage; each ILC subset is activated by different cytokines (see Fig. 1).
Fig1. Cytokine producing innate lymphoid cell subsets. The three major subsets of cytokine-producing innate lymphoid cells (ILCs) develop from the common lymphoid progenitor that also gives rise to B and T lymphocytes and natural killer (NK) cells (not shown). A common ILC precursor identified by the Id2 transcription factor differentiates into three major subsets of cytokine-producing ILCs. Each differentiated subset is distinguished by expression of distinct transcription factors and by cytokines produced when activated, as indicated. The cytokines that drive differentiation into ILC1, 2, or 3 subsets, as well as the cytokines that activate ILCs to produce their own subset-specific cytokines, are shown. The major known functions of the ILCs are also indicated. The cytokines indicated in bold are discussed in Chapter 10, in the con text of T-cell responses. The functions of the other cytokines mentioned in the figure are summarized later in this chapter (see Table 1), and all these cytokines are listed in Appendix I. IFN, Interferon; IL, interleukin; TSLP, thymic stromal lymphopoietin.
Table1. Cytokines of Innate Immunity
ILC subsets may participate in host defense against various pathogens and also may be involved in inflammatory disorders. ILC1s are likely important for defense against intracellular microbes. ILC2s may play a role in defense against helminthic parasites and also contribute to allergic diseases. ILC3s are found at mucosal sites and participate in defense against extra cellular fungi and bacteria, as well as in maintaining the integrity of epithelial barriers. Lymphoid tissue–inducer (LTi) cells are a subtype of ILC3s, which, in addition to secreting IL-17 and IL-22, also express the membrane molecule lymphotoxin and secrete TNF, both of which are required for the normal development of lymphoid organs.
The feature of ILCs that makes them potentially important for early host defense is that they are resident in epithelial barrier tissues, poised to react against microbes that breach these barriers. By contrast, T cells circulate through secondary lymphoid organs and migrate into tissues only after they are activated and differentiate into effector cells, a process that may take several days after encounter with a microbe. Because corresponding subsets of ILCs and helper T cells produce similar cytokines, they may work in a temporally coordinated way, with ILCs being the early innate participants, activated by alarmins in infected tissues, and the helper T cells appearing later as part of adaptive immunity. The actions of ILC1s, NK cells, and Th1 cells are sometimes grouped under type 1 immunity (along with activated CD8+ T cells, discussed in later chapters), ILC2s and T h2 cells are type 2 immunity; ILC3s and Th17 cells comprise type 3 immunity. In general, although ILCs may contribute to the early cytokine response, effector T cells rapidly become the dominant participants because they are more numerous and make much larger amounts of cytokines. The contribution of ILCs to host defense has been difficult to establish because it has not been possible to selectively eliminate these cells or their cytokines in experimental animals without having an impact on the analogous T lymphocytes as well. The role of ILCs in host defense and inflammatory diseases in humans is also uncertain because these cells are numerically rare in blood and therefore difficult to study.
