Innate Lymphoid Cells (ILCs): Cytokine Hubs Regulating Immunity and Tissue Homeostasis

Abstract

Innate lymphoid cells (ILCs) have emerged as an expanding family of effector cells particularly enriched in the mucosal barriers. ILCs are promptly activated by stress signals and multiple epithelial- and myeloid-cell-derived cytokines. In response, ILCs rapidly secrete effector cytokines, which allow them to survey and maintain the mucosal integrity. Uncontrolled action of ILCs might contribute to tissue damage, chronic inflammation, metabolic diseases, autoimmunity, and cancer. Here we discuss the recent advances in our understanding of the cytokine network that modulate ILC immune responses: stimulating cytokines, signature cytokines secreted by ILC subsets, autocrine cytokines, and cytokines that induce cell plasticity.

Figure 1.

Cytokines involved in mouse and human innate lymphoid cells (ILCs) development. All ILCs are derived from a common lymphoid progenitor (CLP). In the mouse, interleukin (IL)-7 is essential for the development of ILC2, ILC3, and lymphoid tissue inducer (LTi) cells, and IL-15 is required for development of natural killer (NK) cells. IL-15 is important for ILC1 development but some ILC1 can develop independent of IL-15. For humans, IL-7 and IL-15 also play an important role in ILC and NK-cell development, and some studies indicate the involvement of IL-1β as, thus far, identified ILC progenitors (ILCPs) all express its receptor. α-LP, α-Lymphoid progenitor; EILP, early innate lymphoid progenitor; CHILP, common helper-like ILC progenitor; PLZF, promyelocytic leukemia zinc-finger protein; NKp, NK progenitor; cNK, conventional NK.

Figure 2.

Innate lymphoid cell (ILC) subsets and cytokines. ILC1s depend on transcription factor T-bet for their function and produce interferon (IFN)-γ and tumor necrosis factor (TNF)-α in response to interleukin (IL)-12, IL-15, and IL-18 derived from dendritic cells (DCs). ILC2s require GATA3 and are endowed with the ability to secrete IL-4, IL-5, IL-9, IL-13, and amphiregulin (Areg) in response to IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) derived from epithelial cells and tissue-resident immune cells. ILC3s depend on the transcription factor RAR-related orphan receptor γt (RORγt) and secrete IL-17, IL-22, and granulocyte macrophage colony-stimulating factor (GM-CSF) in response to IL-23, IL-1β, and IL-1α derived from macrophages and DCs. ILC immune responses are shaped to cope with different types of pathogens, although their dysregulation might lead to chronic inflammation. SC, Stromal cell; EC, epithelial cell; Eos, eosinophils; GC, goblet cell.

Figure 3.

Innate lymphoid cell (ILC) plasticity is governed by the cytokine milieu. ILCs can switch between fully polarized subsets to rapidly adapt to changes occurring in their environment. (A) Interleukin (IL)-12 and IL-18 drives the transdifferentiation of ILC3s into ILC1s. This process is reversible because ILC1s convert to ILC3s in the presence of IL-23 and IL-1β. ILC2s undergo cell plasticity in the presence of IL-1β and IL-12 to convert into interferon (IFN)-γ-secreting ILC1s. IL-4 can revert this transdifferentiation process and convert ILC1s into ILC2s. (B) Double hit model of ILC2s plasticity. ILC2s require of two types of signals to undergo transdifferentiation. Signal 1, secreted by epithelial cells on stress or damage conditions, is induced by IL-1 family members and trigger modifications in the chromatin architecture. DNA reprogramming will be orchestrated by the signal 2 or “driving cytokines.” IL-12 drives ILC2s plasticity toward ILC1s to better cope with intracellular bacteria or virus, whereas IL-4 enhances type 2 immune responses against helminths.