Cytokine Networks between Innate Lymphoid Cells and Myeloid Cells

Abstract

Innate lymphoid cells (ILCs) are an essential component of the innate immune system in vertebrates. They are developmentally rooted in the lymphoid lineage and can diverge into at least three transcriptionally distinct lineages. ILCs seed both lymphoid and non-lymphoid tissues and are locally self-maintained in tissue-resident pools. Tissue-resident ILCs execute important effector functions making them key regulator in tissue homeostasis, repair, remodeling, microbial defense, and anti-tumor immunity. Similar to T lymphocytes, ILCs possess only few sensory elements for the recognition of non-self and thus depend on extrinsic cellular sensory elements residing within the tissue. Myeloid cells, including mononuclear phagocytes (MNPs), are key sentinels of the tissue and are able to translate environmental cues into an effector profile that instructs lymphocyte responses. The adaptation of myeloid cells to the tissue state thus influences the effector program of ILCs and serves as an example of how environmental signals are integrated into the function of ILCs via a tissue-resident immune cell cross talks. This review summarizes our current knowledge on the role of myeloid cells in regulating ILC functions and discusses how feedback communication between ILCs and myeloid cells contribute to stabilize immune homeostasis in order to maintain the healthy state of an organ.

Keywords: Group 1 ILCs; ILC2; ILC3; cytokines; dendritic cells; innate lymphoid cells; macrophages; myeloid cells.

Figure 1

Development and functional specialization of innate lymphoid cells (ILCs). The diagram shows the developmental pathways of ILCs and branching into their different lineages. The early innate lymphoid precursor (EILP) and the common helper innate lymphoid precursor (CHILP) are progenitors to all ILCs (36, 37). Critical lineage-determining transcription factors are shown. Arising ILCs [natural killer (NK) cells, lymphoid tissue inducer (LT) cells, ILC1–3, and ILCreg] are displayed, including arising subsets. Individual groups of ILCs are indicated through color schemes. The expression of natural cytotoxicity receptors (NCRs) on ILC subsets is indicated. Specific and shared effector cytokines secreted during inflammation and steady state are listed below the indicated subsets of ILCs. Documented plasticity within group 2 ILCs and group 3 ILCs is indicated using overlapping and colored bubbles.

Figure 2

Myeloid regulation of innate lymphoid cells (ILCs) function and plasticity. (A) Dendritic cells (DCs) activate natural killer (NK) cells, group 1 ILCs (ILC1), ex-ILC3/ILC1 through interleukin (IL)-12, IL-15, and IL-23. (B) Natural cytotoxicity receptor (NCR)-expressing ILC subsets are subject to receptor-ligand mediated activation or inhibition. Improved immune responses through re-occurring engagement of activating receptors have been associated with memory-like behavior in NK cells. Co-stimulatory receptors and checkpoint inhibitory ligands could control the interactions of macrophages/DCs and ILCs. (C) Monocyte/macrophages inhibit NK cells via IL-10 and TGF-β secretion. (D) DC subsets are capable of activating ILC2 through the production of IL-33, thymic stromal lymphopoietin (TSLP), and TL1A. (E) PMN leukocytes (basophils and mast cells) activate ILC2 through IL-33, IL-4, and lipid mediators. (F) DC subsets and macrophages influence the stability of ILC2 by inducing type 1 immune features through IL-12, IL-1, and IL-27 leading to plastic behavior of ILC2. (G) ILC3 are activated by monocyte/macrophages and DCs. Lipid mediators and the cytokines IL-1β, IL-23, and TL1A drive ILC3 effector functions. (H) Retinoic acid, IL-23, IL-15, and IL-12 are myeloid-derived cytokines that control the plasticity and transition of NCR⁺ILC3 and ex-RORγtILC3/ILC1.

Figure 3

Summary of ILC-mediated myeloid cell activation on immunity and physiology. (A) Natural killer (NK) cells, Group 1 ILCs (ILC1), and ex-RORγt ILC3/ILC1 control the migration of monocyte/macrophages and neutrophils, modulate their anti-microbial activity and anti-tumor response leading to sustained inflammation. (B) ILC2-derived cytokines act on eosinophils, dendritic cells (DCs), and macrophages to control their proliferation, migratory behavior, role in tissue remodeling and repair. Furthermore, ILC2-mediated activation of myeloid cells is essential in anti-parasitic immunity and optimization of Th2 priming. (C) ILC3s control the recruitment, motility, and tissue repair through the activation of DC/macrophages, eosinophils, and neutrophils. The anti-bacterial immunity driven by ILC3-produced cytokines contributes to host-defense, while homeostatic execution of ILC3-specific effector functions improves T cell priming and innate B cell responses.