Helper-Like Type-1 Innate Lymphoid Cells in Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD) is an idiopathic condition characterized by chronic relapsing inflammation in the intestine. While the precise etiology of IBD remains unknown, genetics, the gut microbiome, environmental factors, and the immune system have all been shown to contribute to the disease pathophysiology. In recent years, attention has shifted towards the role that innate lymphoid cells (ILCs) may play in the dysregulation of intestinal immunity observed in IBD. ILCs are a group of heterogenous immune cells which can be found at mucosal barriers. They act as critical mediators of the regulation of intestinal homeostasis and the orchestration of its inflammatory response. Despite helper-like type 1 ILCs (ILC1s) constituting a particularly rare ILC population in the intestine, recent work has suggested that an accumulation of intestinal ILC1s in individuals with IBD may act to exacerbate its pathology. In this review, we summarize existing knowledge on helper-like ILC1 plasticity and their classification in murine and human settings. Moreover, we discuss what is currently understood about the roles that ILC1s may play in the progression of IBD pathogenesis.

Keywords: inflammation; inflammatory bowel disease; innate lymphocyte cells; intestine; natural killer cell; type 1 innate lymphoid cells.

Figure 1

Helper-like type 1 ILCs (ILC1s) in homeostasis and intestinal inflammation. (A) ILC1s comprise of lamina propria (LP) ILC1s, intra-epithelial (ie) ILC1s, and cytotoxic ILC1s/tissue-resident (tr) natural killer cells. In the healthy intestinal microenvironment, ILC1s are the least frequent ILC population. In inflammatory bowel disease (IBD), the frequency of ILC1s is increased at the expense of ILC3s and ILC2s. ILC3s and ILC2s transdifferentiate into ILC1s aided by the secretion of IL-12 from dendritic cells. Ex-ILC3s can secrete both IFN-γ and IL-22 upon stimulation, while ex-ILC2s can produce both IFN-γ and IL-13. The increase in ILC1 frequency leads to an increase in pro-inflammatory cytokine secretion and augmented levels of ILC1-derived TGF-β1. TGF-β1 has been shown to increase CD44v6⁺ expression in epithelial and mesenchymal cells. In homeostasis, this may aid wound healing; however, in IBD this is associated with enhanced fibronectin-1 deposition and extracellular matrix degradation, consequently promoting tissue scarring. Abundant levels of IFN-γ disrupt the epithelial tight junctions, leading to increased epithelial permeability. This allows commensal, pathogenic, and opportunistic bacterial species (such as Bacteroides fragilis, Escherichia coli, Mycobacterium avium subsp. paratuberculosis, and C. difficile) to penetrate the lamina propria, thus perpetuating the inflammation. (B) Figure key illustrating the different cell types and molecules participating in intestinal inflammation. IFN-γ, interferon-gamma; IL-22, interleukin-22; IL-17, interleukin-17; IL-13, interleukin-13; IL-12, interleukin-12; TGF-β1, transforming growth factor-beta 1; TNF-α, tumor necrosis factor-alpha; PRF, perforin; GrzB, granzyme-B; GNLY, granulysin.