Innate Lymphoid Cells in Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract with rising incidence and an unclear etiology. Innate lymphoid cells (ILCs) have recently emerged as key regulators of mucosal immunity and tissue homeostasis and are increasingly implicated in IBD. Unlike adaptive lymphocytes, ILCs do not require antigen recognition and clonal expansion to respond rapidly to environmental cues and shape immune responses. In a healthy gut, ILCs maintain intestinal homeostasis by guarding the epithelial barrier, protecting against pathogens, and mounting proper responses to external insults. However, their altered differentiation, proliferation, recruitment, activation, and interaction with other host cells, microbiota, and environmental stimuli may contribute to IBD. In this review, we discuss recent advances in understanding murine and human ILCs in the context of intestinal inflammation and IBD. A deeper understanding of ILC-mediated immune mechanisms may offer novel therapeutic strategies for restoring intestinal homeostasis and improving personalized management of IBD.

Keywords: animal models; inflammatory bowel disease; innate lymphoid cells; mucosal immunity; novel therapies.

Figure 1

ILC classification and differentiation. In humans and mice, ILCs originate from lymphoid progenitors such as CLPs and LMPPs. Human CLPs initially emerge in the fetal liver before transitioning to the adult bone marrow as the primary site of development. ILC differentiation follows a well-defined hierarchical pathway. CLPs give rise to CILPs, which serve as the earliest precursors within the ILC lineage. CILPs can develop into functional NK cells. Alternatively, CILPs differentiate through the CHILP lineage, giving rise to ILCPs and LTiPs, which further mature into LTis. LTis play a critical role in lymphoid organogenesis, whereas ILCPs differentiate into ILC1s, ILC2s, and ILC3s with distinct functions. Abbreviations: CLP, common lymphoid progenitor; LMPP, lymphoid-primed multipotent progenitor; CILP, common innate lymphoid progenitor; CHILP, common helper-like innate lymphoid progenitor; ILCP, innate lymphoid cell precursor; LTiP, lymphoid tissue inducer progenitor; Eomes, eomesodermin; T-bet, T-box expressed in T cells; GATA3, GATA binding protein 3; RORγt, RAR-related orphan receptor gamma t. Created in BioRender. Cao, S. https://BioRender.com/be3izfi (accessed on 27 May 2025). Used with permission.

Figure 2

Role of ILCs in intestinal homeostasis and IBD in mouse models. Intestinal ILCs maintain mucosal homeostasis through coordinated interactions with the epithelium, microbiota, dietary factors, and other immune cells. In the healthy gut, ILC1s produce IFN-γ to support host defense against intracellular pathogens. ILC2s secrete IL-5, IL-13, and AREG, promoting mucus production of goblet cells and tissue repair. ILC3s express IL-22, which enhances epithelial barrier function and antimicrobial defense. In the context of IBD, dysregulated ILC responses contribute to epithelial injury and chronic inflammation. ILC1s show increased production of IFN-γ and granzymes, while ILC2 activity becomes exaggerated. ILC3s exhibit functional plasticity and context-dependent roles in IBD, contributing to either mucosal protection or inflammation depending on the local immune milieu. Moreover, as key sensors of dietary stress, ILCs are regulated by multiple environmental cues, including micronutrient availability, dietary components, and changes in the gut microbiota. Abbreviations: ILC, innate lymphoid cell; iILC3: inflammatory ILC3; AHR, aryl hydrocarbon receptor; AREG, amphiregulin; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN-γ, interferon-gamma; IL, interleukin; MMP9, matrix metalloproteinase 9; OX40L, OX40 ligand; TNF, tumor necrosis factor; TSLP, thymic stromal lymphopoietin; Treg, regulatory T cell; VIP, vasoactive intestinal peptide; KD, ketogenic diet; LCD, low-carbohydrate diet; HFD, high-fat diet; NCR, natural cytotoxicity receptor. Created in BioRender. Cao, S. (2025) https://BioRender.com/wuwrb6n (accessed on 27 May 2025). Used with permission.