Orchestration of intestinal homeostasis and tolerance by group 3 innate lymphoid cells

Abstract

The gastrointestinal tract is the primary site of exposure to a multitude of microbial, environmental, and dietary challenges. As a result, immune responses in the intestine need to be tightly regulated in order to prevent inappropriate inflammatory responses to exogenous stimuli. Intestinal homeostasis and tolerance are mediated through a multitude of immune mechanisms that act to reinforce barrier integrity, maintain the segregation and balance of commensal microbes, and ensure tissue health and regeneration. Here, we discuss the role of group 3 innate lymphoid cells (ILC3) as key regulators of intestinal health and highlight how increasing evidence implicates dysregulation of this innate immune cell population in the onset or progression of a broad range of clinically relevant pathologies. Finally, we discuss how the next generation of immunotherapeutics may be utilized to target ILC3 in disease and restore gastrointestinal tolerance and tissue health.

Keywords: Commensal bacteria; Dietary antigens; ILC; Inflammation; Inflammatory bowel disease; Innate lymphoid cells; Mucosal tolerance.

Fig. 1

Group 3 innate lymphoid cells are central orchestrators of intestinal immune tolerance. The intestinal tract is host to a wide range of exogenous antigenic stimuli derived from microbial and dietary sources. Group 3 innate lymphoid cells (ILC3) are present constitutively in the intestine and have central roles in maintaining tolerance and tissue homeostasis. In particular, one subset of ILC3 (LTi-like ILC3) possess multiple mechanisms to regulate immune responses and reinforce intestinal barrier function in the intestinal tissue and associated lymphoid structures. Intestinal ILC3 are a dominant source of interleukin (IL)-22 at steady state, produced in response to microbially driven cytokine cues provided by tissue-resident myeloid cells. IL-22 acts to reinforce epithelial barrier tight junctions and induce antimicrobial peptides, mucus production, and fucosylation of the epithelial cells to maintain segregation of commensal microbes. In addition, ILC3 act either indirectly (via cytokine effects on intermediary cells) or directly (via cell–cell contact) to control the quality and magnitude of the adaptive immune response. Together, intestinal ILC3 represent an important cellular regulator of intestinal tissue health

Fig. 2

Dysregulated ILC3 responses precipitate the onset and progression of gastrointestinal disease. A broad range of intestinal pathologies are inherently associated with a loss of intestinal tolerance and dysregulated inflammatory immune responses. Dysregulation of intestinal ILC3 numbers and functions has been implicated in the pathogenesis and progression in multiple clinically relevant diseases including inflammatory bowel disease (IBD), HIV infection, graft-versus-host disease (GVHD), and colorectal cancer (CRC). These pathologies have been associated with a loss of ILC3-intrinsic homeostatic functions including antigen-presenting function and IL-22 production and subsequent failure to maintain the intestinal barrier—resulting in antigen translocation and sensitization of the underlying immune system and aberrant inflammatory T cell responses. Furthermore, dysregulation of IL-22 signaling leads to epithelial hyperplasia that can progress to colorectal cancer in the presence of chronic inflammation. Thus, therapeutic strategies to restore homeostatic ILC3 functions may prove efficacious in intestinal inflammatory disorders. In addition, NCR-expressing ILC3 (NCR⁺ ILC3) exhibit a degree of functional and transcriptional plasticity and in the presence of an inflammatory cytokine milieu lose RORγt expression to become ILC1-like “ex-ILC3,” a phenotype associated with production of pro-inflammatory cytokines such as IFN-γ and which has been implicated in driving intestinal pathology and tissue damage in IBD. Thus, therapeutic interventions to suppress inflammatory ILC3 may offer a novel strategy to promote resolution of disease in multiple intestinal disorders