Activation and Suppression of Group 3 Innate Lymphoid Cells in the Gut

Abstract

Group 3 innate lymphoid cells (ILC3s) have emerged as master regulators of intestinal health and tissue homeostasis in mammals. Through a diverse array of cytokines and cellular interactions, ILC3s crucially orchestrate lymphoid organogenesis, promote tissue protection or regeneration, facilitate antimicrobial responses, and directly regulate adaptive immunity. Further, translational studies have found that ILC3 responses are altered in the intestine of defined patient populations with chronic infectious, inflammatory, or metabolic diseases. Therefore, it is essential to broadly understand the signals that activate, suppress, or fine-tune ILC3s in the gut. Here, we discuss recent exciting advances in this field, integrate them into our current understanding of ILC3 biology, and highlight fundamental gaps in knowledge that require additional investigation.

Figure 1. Activation signals of ILC3s.

Environmental signals in the GI tract from microbiota, pathogens, neurons, and diet directly or indirectly activate ILC3s. Here, we propose that these can be grouped into three main themes. (1) Metabolites derived from microbiota or the diet (such as oxysterols, SCFAs, AhR ligands and Ras), and circadian rhythms that modulate ILC3 development, homing receptor expression, and IL-22 production, thereby maintaining ILC3 homeostasis. (2) Myeloid-derived IL-23 which serves as a master regulator of IL-22 and IL-17 production in ILC3s, enhancing the antimicrobial defense and barrier integrity of the intestine. Cytokines including TL1A, IL-18, IL-6, and IL-1, and neurotrophic factor GDNF fine-tune IL-22 production. (3) IL-1β released by macrophages, which stimulates IL-2 expression and GM-CSF production by ILC3s, orchestrating immune regulation in the intestine.

Figure 2.. Suppression signals of ILC3s.

Signals derived from the epithelium, as well as a result of adaptive and innate immunity, suppress the function of ILC3s. Intestinal epithelial cells release IL-25 and TSLP indirectly inhibiting the production of IL-22 in ILC3s. Both CD4⁺ effector T cells and regulatory T cells are able to indirectly suppress ILC3s through distinct mechanisms. IL-10 signaling in CX3CR1⁺ myeloid cells indirectly repress ILC3s and RANK signaling enables self-regulation of ILC3s. Downward arrows represent suppression.