Regulation of Human Innate Lymphoid Cells in the Context of Mucosal Inflammation

Abstract

Since their identification as a unique cell population, innate lymphoid cells (ILCs) have revolutionized our understanding of immune responses, leaving their impact on multiple inflammatory and fibrotic pathologies without doubt. Thus, a tightly controlled regulation of local ILC numbers and their activity is of crucial importance. Even though this has been extensively studied in murine ILCs in the last few years, our knowledge of human ILCs is still lagging behind. Our review article will therefore summarize recent insights into the function of human ILCs and will particularly focus on their regulation under inflammatory conditions. The quality and intensity of ILC involvement into local immune responses at mucosal sites of the human body can potentially be modulated via three different axes: (1) activation of tissue-resident mature ILCs, (2) plasticity and local transdifferentiation of specific ILC subsets, and (3) tissue migration and accumulation of peripheral ILCs. Despite a still ongoing scientific effort in this field, already existing data on the fate of human ILCs under different pathologic conditions clearly indicate that all three of these mechanisms are of relevance for the clinical course of chronic inflammatory and autoimmune diseases and might likewise provide new target structures for future therapeutic strategies.

Keywords: ILC plasticity; cytokine; human immune system; innate lymphoid cells; mucosal inflammation; tissue migration.

Figure 1

Mechanisms regulating local ILC activity. To adapt ILC functions at mucosal barriers to the respective environmental need, local ILC numbers and their activity can be regulated by soluble mediators or direct cell-cell interactions (green background). To date, cytokines and lipid mediators represent the most commonly described soluble regulators of human ILCs and can be released, for instance, by stress-sensing epithelial cells or other immune cells like mast cells. Furthermore, neurotransmitters and neuropeptides have also been suggested to directly interact with ILCs. In addition, cell-cell contact-dependent regulation of ILCs is based on their interaction with endothelial, stromal, and other immune cells. Upon sensing these signals, ILC activity (orange background) and their local number (yellow background) can be controlled. Tissue ILC counts can be modulated directly by cell death and proliferation or the differentiation of local ILC precursors into mature cells. Moreover, ILCs are plastic cells, enabling the transdifferentiation of one subset into another. Altered local ILC numbers can additionally result from the migration of ILCs either within an organ or from/to a distal site. Representatively, regulators modulating ILC activities on various levels are shown. In vivo, multiple mechanisms controlling local ILC activity are likely to act synergistically, enabling the activation or suppression of ILC activities in a highly controlled fashion. However, dysbalanced and overwhelming ILC responses are often unable to successfully fight pathogens or can even trigger inflammatory diseases.

Figure 2

(Trans-) Differentiation of human ILCs in mucosal tissues. To adapt the local pool of tissue-resident ILCs, mature ILCs can differentiate from local precursors or transdifferentiate into other ILC subsets. This shift in local ILC subgroups is mediated by the local cytokine environment and can be observed in various fibro-inflammatory diseases affecting the lung and gut. CD and severe COPD, for instance, are characterized by an ILC1-dominated immune response. In line with this, human ILC1s can be induced from c-Kit⁺NKp44⁻ ILC precursors as well as from mature ILC2s and ILC3s in these pathologies; this is mainly regulated by IL-12. In contrast, in chronic rhinosinusitis with nasal polyps (CRwNP), ILC2s rather than ILC1s represent important effector cells triggering the immune response. Accordingly, ILC2 plasticity can be suppressed by IL-4 and vitamin D3, hampering the acquisition of ILC1- or ILC3-like characteristics to preserve type-2 immunity. Nevertheless, retinoic acid can trigger ILCreg formation from mature ILC2s, likely representing a negative feedback mechanism to control ILC2 responses. Though characterized by nasal polyps as well, cystic fibrosis patients (CFwNP) display an ILC3-driven phenotype in upper airways that can be induced by TGF-β-driven transdifferentiation of ILC2s into ILC3s. Potentially, ILC1s might also represent a source of mature ILC3s, as shown in vitro in response to IL-23, TGF-β, and retinoic acid. Whether further ILC plasticity exists in humans needs to be targeted in future studies.