Innate lymphoid cell interactions with microbiota: implications for intestinal health and disease

Abstract

The mammalian intestine harbors trillions of beneficial commensal bacteria that are essential for the development of the immune system and for maintenance of physiologic processes in multiple organs. However, numerous chronic infectious, inflammatory, and metabolic diseases in humans have been associated with alterations in the composition or localization of commensal bacteria that result in dysregulated host-commensal bacteria relationships. The mammalian immune system plays an essential role in regulating the acquisition, composition, and localization of commensal bacteria in the intestine. Emerging research has implicated innate lymphoid cells (ILCs) as a critical immune cell population that orchestrates some of these host-commensal bacteria relationships that can impact immunity, inflammation, and tissue homeostasis in the intestine. This review will discuss reciprocal interactions between intestinal commensal bacteria and ILCs in the context of health and disease.

Figure 1. Emerging subsets of innate lymphoid cells

Innate lymphoid cells can be broadly placed into three groups consisting of T-bet⁺ ILCs (group 1), GATA3⁺ ILCs (group 2) and RORγt⁺ ILCs (group 3). These subsets develop from lymphoid progenitor(s), require the transcription factor Id2 and are independent of somatic recombination. Group 1 T-bet⁺ ILCs include Natural Killer (NK) cells and natural cytotoxicity receptor (NCR)⁻ ILCs that are differentially regulated by IL-15 and IL-7 respectively, but respond to IL-12 and IL-18, and produce TNFα and IFNγ. Group 2 GATA3⁺ ILCs are responsive to IL-2, IL-7, IL-25 and IL-33, and produce IL-5, IL-13 and Amphiregulin (Areg). Group 3 RORγt⁺ ILCs are heterogeneous in expression of CD4 and NCRs, responsive to IL-2, IL-7, IL-23 and IL-1β, and produce IL-17A and IL-22. With the exception of IL-5, these ILC-derived effector cytokines can directly influence epithelial cell responses in the intestine.

Figure 2. Direct and indirect regulation of ILC responses by commensal bacteria

Commensal bacteria can influence ILC populations through direct recognition (left) of commensal bacteria or commensal bacteria-derived products by toll-like receptors (TLRs), natural cytotoxicity receptors (NCRs) or the aryl hydrocarbon receptor (AhR). Commensal bacteria can also promote or inhibit ILC populations though indirect recognition (right) of commensal bacteria or commensal bacteria-derived products by resident myeloid or epithelial cells and subsequent cytokine production.

Figure 3. Regulation of commensal bacteria by ILCs

ILCs can regulate both the composition and anatomical location of commensal bacteria through the production of cytokines that influence numerous pathways at the intestinal epithelial cell barrier. T-bet⁺ ILCs produce TNFα and IFNγ which can directly influence intestinal epithelial cell permeability and limit dysbiosis of commensal bacteria. GATA3⁺ ILCs produce IL-13 and amphiregulin (Areg), however a role for these cytokines in regulating commensal bacteria has not yet been identified. RORγt⁺ ILCs produce lymphotoxin (LT)β to promote the generation of isolated lymphoid follicles (ILFs) and support intestinal IgA production. RORγt⁺ ILCs also produce IL-22 to promote epithelial cell production of mucins and anti-microbial proteins (RegIIIβ, RegIIIγ, S100A8 and S100A9), which are critical for maintaining spatial segregation and anatomical containment of commensal bacteria.