Innate lymphoid cells in intestinal immunity and inflammation

Abstract

Innate lymphoid cells (ILCs) are a new and distinct family of innate immune cells that play an important role in immunity and inflammation. In this review, we focus on the role of ILCs in mucosal tissues, especially in the gut, in health and disease. ILCs support intestinal homeostasis by protecting the intestine from pathogens, contributing to the development of gut lymphoid tissue, and helping to repair injuries. By cooperating with epithelial cells and other innate and adaptive immune cells, ILCs participate in the control of pathogens and tolerance of commensal bacteria. The development and maintenance of ILCs are influenced by nutrients and metabolites sourced from diet and/or gut bacteria. ILCs have been shown to be involved in host metabolism and to participate in various diseases of the intestine including infectious and chronic inflammatory diseases, and cancer. Thus, the elucidation of ILC biology provides an exciting potential for development of novel therapeutic means to modulate immune responses in various disease settings.

Keywords: Commensals; Diet; Homeostasis; Metabolism; Nutrition.

Fig. 1

Innate lymphoid cells (ILCs) can be categorized, based on their cytokine production and key transcriptional regulators, into three groups: Group 1—ILC1s (T-bet) and natural killer cells (eomesodermin), Group 2—ILC2s (GATA-3) and Group 3—ILC3s (RORγt). ILCs act quickly upon cytokine stimulation, releasing additional cytokines that facilitate the control of infections and tissue damage. GM-CSF granulocyte macrophage colony-stimulating factor, IFNγ interferon γ, NCR natural cytotoxicity receptor, RORγt RAR-related orphan receptor gamma t, TNF tumor necrosis factor, TSLP thymic stromal lymphopoietin

Fig. 2

By cooperating with epithelial cells and other innate and adaptive immune cells, ILCs participate in the control and tolerance of commensal bacteria. MAMPs (microbe-associated molecular patterns) from commensal bacteria in the intestinal lumen activate epithelial cells and CX3CR1⁺ macrophages, which continuously sample the lumen contents. Additionally, MAMPs and whole bacteria translocate from the lumen into the lamina propria through manifold cells (M cells) located in Peyer’s patches. CD103⁺ dendritic cells take up bacteria and antigen and migrate to the mesenteric lymph nodes, where they interact with T and B cells. In the lamina propria, ILC3s participate in the formation of Peyer’s patches, cryptopatches and isolated lymphoid follicles (ILFs), where immune cells aggregate. Cryptopatches mature into ILFs populated with T, B, and antigen presenting cells that facilitate cell–cell interactions. ILC3-induced ILFs are important nodes for the production of IgA, which is transported through the epithelial cells into the lumen. Although ILC3s are the most numerous ILC population in the intestine, ILC1s and ILC2s also play important roles in gut immunity. Intraepithelial ILC1s produce IFNγ and participate in immunity against intracellular pathogens. ILC2s produce IL-13 which acts on goblet cells, enhancing mucin production during parasite infections. DC dendritic cells, MAMPs microbe-associated molecular patterns

Fig. 3

a ILC1s help protect against intracellular pathogens, viruses, and tumors. IL-15 from intestinal epithelial cells (IECs) induces IFNγ production from ILC1s. IFNγ acts on IECs to increase the expression of the chemokines, CXCL9, CXCL10 and CXCL11, which attract CXCR3⁺ leukocytes, including T helper 1 (Th1) cells, ILC1s and NKp46⁺ ILC3s. Retinoic acid, in cooperation with IL-23 from DCs, increases the expression of RORγt in ILC1s and induces their conversion into ILC3s. b ILC2s protect against helminth invasion, participate in wound healing, and are implicated in allergic responses. Stimulation by IL-25, IL-33 or thymic stromal lymphopoietin (TSLP) induces ILC2s to produce IL-5 and IL-13. IL-13 drives mucus production from goblet cells in the gut, which facilitates helminth expulsion. IL-33 enhances the expression of amphiregulin by ILC2s in the gut. Amphiregulin plays a tissue-protective role in the gut by participating in injury repair. Prostaglandin D2 (PGD2), which is a pro-inflammatory molecule, induces chemotaxis of ILC2s and enhances their expression of type 2 cytokines. c ILC3s are involved in resistance to bacterial and fungal infections, control of the commensal bacteria, and development and repair of lymphoid tissues. IECs can positively regulate ILC3s through the secretion of IL-7, which induces signaling that stabilizes RORγt. Secretion of pro-inflammatory cytokines (e.g. IL-1β and IL-23) by activated antigen presenting cells induces the production of IL-17A, IL-22 and GM-CSF by ILC3s, while IL-12 suppresses ILC3 function and mediates their conversion into ILC1s. IL-17A participates in the recruitment of neutrophils, an important effector cell for extracellular pathogen immunity, by inducing the expression of CXCL1 and CXCL2 by IECs. IL-22 induces the production of antimicrobial peptides in intestinal epithelial cells, which is critical for the containment of commensal. GM-CSF is an important cytokine that participates in the homeostasis of mononuclear phagocytes in the intestine. Additionally, CXCL16 produced by DCs recruits ILC3s which express CXCR6. AREG amphiregulin, DC dendritic cells, IECs intestinal epithelial cells, GM-CSF granulocyte macrophage colony-stimulating factor, IFNγ interferon γ