Dysregulation of Group 3 Innate Lymphoid Cells in the Pathogenesis of Inflammatory Bowel Disease

Abstract

Purpose of review: Here, we review recent literature indicating a role of innate lymphoid cells in human inflammatory bowel disease with a focus on the plastic population of ILC3.

Recent findings: Many studies suggest an involvement of ILC3 in human intestinal inflammation. ILC3 present the most abundant ILC subtype in the human intestine at steady state. In IBD, this composition is skewed towards ILCs showing an ILC1 phenotype and cytokine profile. This change is likely due to the microenvironment causing skewing of the functionally plastic ILC subsets. Interactions between ILCs and other cells are important to keep homeostasis and intestinal barrier integrity. The knowledge about the involvement of ILCs in IBD is rapidly increasing, and with the help of mouse models, new pathways and functions of ILCs are continuously unraveled. In the majority of human studies, a potential role for ILCs in Crohn's disease is found. However, less data is available for a possible role in ulcerative colitis. Results from mice are obtained from diverse model systems, and more research in this field is needed to clarify and integrate the current knowledge in order to improve treatment strategies for IBD patients.

Keywords: ILC3; Inflammatory bowel disease; Innate lymphoid cells; Intestinal homeostasis.

Fig. 1

Classification of human ILCs. Human ILCs are divided into three broad subgroups called group 1, group 2, and group 3 ILCs based on the expression of transcription factors and cytokine production

Fig. 2

ILC3 functions in gut homeostasis. ILC3 are stimulated by IL-23, IL-1β, and TL1A, derived from MNPs and DCs to produce their signature cytokines IL-22 and IL-17 as well as GM-CSF. IL-22 promotes epithelial barrier integrity and proliferation, induces antimicrobial peptide and mucin production and, together with lymphotoxin, enhances epithelial fucosylation. IL-22 production from ILC3 can be also stimulated with epithelial cell-derived PGE₂ whereas dietary AHR ligands help maintain ILC3 in the intestine. IL-17 induces the recruitment of neutrophils and also supports epithelial barrier protection. GM-CSF has been shown to be important in the induction of oral tolerance acting via DCs/MNPs. ILC3 were shown to inhibit commensal-specific T cells via the MHCII receptor together with a withdrawal of IL-2. Epithelial cell-derived IL-25 acts via MNPs/DCs to inhibit ILC3 functions. IL-23, IL-1β, and RA can induce plasticity of ILC1 and ex-ILC3 towards an ILC3 phenotype, whereas IL-12 can reverse this effect under inflammatory conditions

Fig. 3

Changes of ILC frequencies and functions in intestinal inflammation. In the inflamed intestine of Crohn’s patients, several changes in the distribution of ILC frequencies have been observed. Homeostatic NKp44⁺ ILC3 are decreased whereas the frequencies of the IFN-γ-producing subsets of intraepithelial ILC1 and CD127⁺ ILC1 are increased. The IL-12 induced plasticity of NKp44⁺ ILC3 to ex-ILC3, resembling ILC1 is likely contributing to this increased frequency. Somewhat contradictory, NKp44⁺ ILC3 from the colon of UC and CD patients were shown to have a higher capacity for IL-22 production. An IL-17- and IFN-γ-producing CD56⁻ subset of ILC3 was found to be increased in the intestine of Crohn’s patients. In addition, the MHCII expression on intestinal ILC3 from pediatric Crohn’s patients was shown to be reduced and this correlated with an increased number of Th17 cells