Human Gut-Associated Natural Killer Cells in Health and Disease

Abstract

It is well established that natural killer (NK) cells are involved in both innate and adaptive immunity. Indeed, they can recognize molecules induced at the cell surface by stress signals and virus infections. The functions of NK cells in the gut are much more complex. Gut NK cells are not precisely organized in lymphoid aggregates but rather scattered in the epithelium or in the stroma, where they come in contact with a multitude of antigens derived from commensal or pathogenic microorganisms in addition to components of microbiota. Furthermore, NK cells in the bowel interact with several cell types, including epithelial cells, fibroblasts, macrophages, dendritic cells, and T lymphocytes, and contribute to the maintenance of immune homeostasis and development of efficient immune responses. NK cells have a key role in the response to intestinal bacterial infections, primarily through production of IFNγ, which can stimulate recruitment of additional NK cells from peripheral blood leading to amplification of the anti-bacterial immune response. Additionally, NK cells can have a role in the pathogenesis of gut autoimmune inflammatory bowel diseases (IBDs), such as Crohn's Disease and Ulcerative Colitis. These diseases are considered relevant to the generation of gastrointestinal malignancies. Indeed, the role of gut-associated NK cells in the immune response to bowel cancers is known. Thus, in the gut immune system, NK cells play a dual role, participating in both physiological and pathogenic processes. In this review, we will analyze the known functions of NK cells in the gut mucosa both in health and disease, focusing on the cross-talk among bowel microenvironment, epithelial barrier integrity, microbiota, and NK cells.

Tissue Determinants of Human NK Cell Development, Function, and Residence

“…Intestines also harbor immature subsets, but maintain predominantly two specific types not found in blood or other tissues that are also found in gut-associated LN. One of the intestine-specific subsets exhibits co-expression of NKp44 and NKp46 and may resemble NK cell phenotypes associated with inflammatory bowel disease (Poggi et al, 2019). Interestingly, the blood, BM, and spleen contain a range of NK cell subsets and differentiation states expressing a range of KIRs, NCRs, and activating receptors, consistent with previously defined heterogeneity among blood NK cells (Bengsch et al, 2018;Horowitz et al, 2013), while lung is enriched in highly differentiated NK cells.…”

Natural Killer Cells in Systemic Autoinflammatory Diseases: A Focus on Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome

“…Nevertheless, in a dextran sulfate sodium (DSS)-induced mouse model of UC, NKG2D + NK cells were found to be decreased in the lamina propria during active disease, proposing a regulatory role for NK cells in this mouse model of UC (85). In general, NK cells are thought to have a dual role in gut inflammation with a pathogenic role in Crohn's disease and UC via cytotoxic activity and cytokine secretion, and a protective role against the development of cancer (90,93).…”

“…In patients with Crohn's disease, NKp46 + mucosal NK cells were increased which produced IFN-γ upon IL-23 stimulation. In contrast, in patients with UC, NKp44 + IL-22producing mucosal NK cells were elevated (86,90). The potential pathogenic or protective role of these NK cells in chronic gut inflammation is still unknown (90).…”

“…In contrast, in patients with UC, NKp44 + IL-22producing mucosal NK cells were elevated (86,90). The potential pathogenic or protective role of these NK cells in chronic gut inflammation is still unknown (90). A potential pathogenic role for NK cells in Crohn's disease was established via the successful treatment of patients with Crohn's disease with anti-NKG2D antibody (91).…”

Metagenomic Analysis of the Gut Microbiome in Psoriasis Reveals Three Subgroups with Distinct Host-Microbe Interactions

“…4B). Although PSO3 patients possess some similarities in gene expression signature to IBD, PSO3 patients have less abundant colonic NK cells and activated CD4 + T cells, which are thought to be key contributors to IBD through cytokine production [42]. Interestingly, increased mucosal CD8 + T cell frequency has been reported in patients with Crohn's disease [43] and CD8 + T cells can trigger intestinal in ammation in mice colitis model [44].…”