Group 3 Innate Lymphoid Cells Inhibit T-Cell-Mediated Intestinal Inflammation through Aryl Hydrocarbon Receptor Signaling and Regulation of Microflora

Abstract

SUMMARY Aryl hydrocarbon receptor (Ahr) is crucial for the maintenance and function of group 3 innate lymphoid cells (ILCs), which are important in gut immunity. Because Ahr promotes T helper 17 (Th17) cell differentiation in vitro, it is reasonable to expect that Ahr would enhance Th17 cells in vivo. Instead, we show that Ahr deficiency caused increased intestinal Th17 cells, raising the possibility that group 3 ILCs could negatively regulate Th17 cells. Reduced innate interleukin-22 (IL-22) in Ahr-deficient mice allowed expansion of commensal segmented filamentous bacteria (SFB), known to promote Th17 cells. Compared to Rorc+/+Ahr−/− mice, Rorcgfp/+Ahr−/− mice had further reduced group 3 ILCs and were prone to spontaneous colitis with increased SFB and Th17 cells. Innate expression of Ahr played a protective role in T-cell-mediated experimental colitis by suppressing pathogenic Th17 cells. Our data reveal an intricate balance between ILCs and Th17 cells regulated by Ahr and commensal flora.

Type 2 Innate Lymphoid Cells Drive CD4+ Th2 Cell Responses

“…This effect also appeared to involve an MHC class II-dependent mechanism; however, and in contrast to the data reported in this article, ILC3 appeared to limit, rather than promote, Th17 cell activation (24). Thus, different classes of ILC can interact with and directly modulate the activation of T cells in vivo.…”

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…Vitamin A deprivation results in a loss of intestinal ILC3 in adult mice, which can be reversed upon supplementation of diet with the vitamin A‐derived metabolite retinoic acid 44, 45. Similarly, Ahr acts to sense soluble aromatic hydrocarbons – present in the diet and produced by commensal bacteria – and is essential for the development of both LTi‐like and NKp46 + ILC3, as well as IL‐22 production 14, 27, 28, 46, 47, 48, 49, 50, 51. Together these signals tune ILC3 numbers and responses and establish bidirectional interactions between ILC3 and the commensal microbiota during the initial colonization of barrier tissue sites.…”

“…Mice with disrupted ILC3‐derived IL‐22 responses exhibit altered gut microbiota and increased susceptibility to experimentally induced colitis 49, 80, 81, 82. Most notably, expansion of segmented filamentous bacteria (SFB) – a canonical Th17‐inducing commensal species – occurs in the absence of ILC3 responses 49.…”

“…Most notably, expansion of segmented filamentous bacteria (SFB) – a canonical Th17‐inducing commensal species – occurs in the absence of ILC3 responses 49. ILC3‐derived IL‐22 induced by SFB colonization stimulates serum amyloid protein production from epithelial cells that drive the recruitment of Th17 cells to the ileum, which subsequently act to control SFB burdens 83.…”

Reciprocity in Microbiome and Immune System Interactions and its Implications in Disease and Health

“…IL-22 from innate immune cells can regulate Th17 cell responses. Reduced levels of IL-22 in innate immune cells in AhR deficient mice result in the expansion of SFB in the gut and subsequent expansion of Th17 cells in the intestine leading to colitis development [121].…”