Dietary Derived Micronutrients Modulate Immune Responses Through Innate Lymphoid Cells

Abstract

Innate lymphoid cells (ILCs) are a group of innate immune cells that possess overlapping features with T cells, although they lack antigen-specific receptors. ILCs consist of five subsets-ILC1, ILC2, ILC3, lymphoid tissue inducer (LTi-like) cells, and natural killer (NK) cells. They have significant functions in mediating various immune responses, protecting mucosal barrier integrity and maintaining tissue homeostasis in the lung, skin, intestines, and liver. ILCs react immediately to signals from internal and external sources. Emerging evidence has revealed that dietary micronutrients, such as various vitamins and minerals can significantly modulate immune responses through ILCs and subsequently affect human health. It has been demonstrated that micronutrients control the development and proliferation of different types of ILCs. They are also potent immunoregulators in several autoimmune diseases and play vital roles in resolving local inflammation. Here, we summarize the interplay between several essential micronutrients and ILCs to maintain epithelial barrier functions in various mucosal tissues and discuss their limitations and potentials for promoting human health.

Keywords: AhR ligands; homeostasis regulation; innate lymphoid cells; micronutrients; mucosal protection; vitamin A and D.

Figure 1

Dietary micronutrients have various and sophisticated programs to mediate the development, proliferation, and functions of ILCs. Dietary sources of micronutrients: AhR ligands, vitamin A and its metabolites, retinoic acid (RA) and all-trans RA (atRA). These micronutrients interact with ILC subsets: ILC1s, ILC2s, ILC3s in the intestine, pancreas, liver, and lung. AhR signaling (indicated as purple arrows): AhR ligands maintain the liver-resident ILC1s/NK cells. AhR is highly expressed by gut ILC2s and inhibits Gfi1 and Tcf7 gene expression, while sustaining ILC3s to control the ILC2-ILC3 balance (shown in the purple dotted line and the purple arrow between the ILC2 and ILC3). In ILC3s, both AhR and RORγt bind to the Il22 locus (yellow ovals in the ILC3) and promote IL-22 and antimicrobial peptide secretion (green arrows and dots). AhR ligands bind to AhR and enhance ILC3s to secrete IL-22 and prevent intestinal epithelial cells (IECs) from becoming transformed via the DNA damage response (DDR) (as shown in the purple dotted line). AhR ligands may also directly act on IECs to prevent malignant transformation. Vitamin A/RA signaling (indicated as red arrows and atRA as yellow arrows): RA induces the expression of gut-homing receptors CCR9 and α4β7 on both ILC1s and ILC3s and guides them to migrate to the gut. RA can also convert some airway ILC2s to regulatory ILCs (ILCreg), which express IL-10, in the inflamed tissues in the presence of the cytokines IL-33 and IL-2. In pancreatic-islets, IL-33 activates local ILC2s and the IL-33-ILC2 axis imprints RA-producing activity in DCs or macrophages and promotes insulin secretion by β cells. RA and atRA promote IL-22-producing NCR⁺ ILC3s and IL-17-producing ILC3s. A vitamin A-deprived diet enhances ILC2 functions and associated cytokines, including IL-4, IL-5, and IL-13 (indicated in red arrow between the ILC2 and ILC3), and showed resistance to parasitic infection. Meanwhile, the vitamin A-deprived diet suppresses ILC3s and their cytokines (red-dotted line between the ILC2 and ILC3). Solid lines represent the enhanced signaling pathways, while the dotted lines represent the suppressed signaling pathways.