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Key features:
Group 3 ILCs (ILC3) are remarkably similar to CD4+ Th17 cell
Stimuli:
Interleukin-1 (IL-1) beta (IL-1F2), Interleukin-23 (IL-23), TNF-like ligand 1 A (TL1A) / Vascular endothelial growth inhibitor, Short-Chain Fatty Acids (SCFAs), AHR Ligands
Effector molecules:
Granulocyte-macrophage colony-stimulating factor (GM-CSF), Interleukin-2 (IL-2), Interleukin-17 Family / Interleukin-17 (IL-17), Interleukin-22 (IL-22)
Major effects:
Maintenance of Group 3 ILCs (ILC3), Group 3 ILCs (ILC3) Expansion and proliferation, Homeostasis of Regulatory T Cells (Tregs), Regulation of CD4 responses in the gut via MHC Class II Group 3 ILCs (ILC3)
Group 3 innate lymphoid cells (ILC3s) are key immune components in the gut located in the intestinal microenvironment. They maintain gut homeostasis by expressing molecules like interleukin (IL)-22 and major histocompatibility complex class II (MHCII). ILC3s support immune tolerance and protect against pathogens. Aberrant ILC3 activity can lead to disease.
While Group 3 ILCs (ILC3) produce IL-22 , IL-17A and Interleukin-17F (IL-17F)(brain://x3_rdyK3A0qdZ0lNEY4fug/Il17f), Lymphoid Tissue Inducer Cells (LTi cells) are mainly involved in lymphoid organ formation through the production of lymphotoxins
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Ganal-Vonarburg & Duerr 2021 Immunology 159: 39-51
A dialogue between ILC3s and T cells via the Major Histocompatibility Complex Class II (MHC-II) is necessary to support colonization with microbiota, which then induce type 1 immunity in the gut and in the tumor microenvironment. People with dysregulated intestinal ILC3s harbor microbiota that, when transferred to mice, do not induce type 1 immunity and immunotherapy responsiveness
Tissue-resident ILC3s promote tolerance. ILC3s from the circulation infiltrates the Central Nervous System (CNS) during neuroinflammation based on mouse experiments. ILC3s infiltrate the CNS in a mouse model of Multiple Sclerosis (MS). These ILC3s are derived from the circulation, localize in proximity to infiltrating T cells in the CNS (pro-inflammatory T cells), function as antigen-presenting cells that restimulate myelin-specific T cells, and are increased in individuals with Multiple Sclerosis (MS) (neuroinflammation). Conventional and tissue-resident ILC3s in the periphery do not appear to contribute to disease (Multiple Sclerosis) induction
IL-22 is predominantly produced by CD4+ T cells and ILC3 populations, among others
Group 3 ILCs are defined by their capacity to produce cytokines Interleukin-17A (IL-17A) and/or IL-22 and Interleukin-23 (IL-23). Group 3 innate lymphoid cells (ILC3s) not only play a protective role in maintaining intestinal homeostasis and gut barrier function, but also a pathogenic role in intestinal inflammation
Among the Innate lymphoid cells (ILCs), Group 3 ILCs (ILC3) are the most important with regard to the gut microbiota. Also, Type 3 ILCs exist mainly in mucosal tissue and at low levels in the spleen and liver. Group 3 ILCs (ILC3) can control the activation of autoreactive CD4+ T cells in the lamina propria by expressing the major histocompatibility complex II (MHC-II). They can drive immune tolerance in the host gut by controlling the function of other immune cells.
The Group 3 ILCs (ILC3) produce neurotrophic factor signals after interacting with enteric glial cells
ILC3s have emerged as a critical subset in the gut. They are the most phenotypically diverse ILC population and interact directly with numerous different cell types (haematopoietic and non-haematopoeitic), as well as interface with the bacterial flora
Group 3 ILCs (ILC3) are dependent on the RAR-related orphan receptor gamma/t (ROR-gamma/t) Isoform 2 (NR1F3) and the aryl hydrocarbon receptor (AHR) and release Interleukin-17 Family / Interleukin-17 (IL-17) and IL-22
Type 3 ILCs express Interleukin-1 (IL-1) receptors (IL-1R) and Interleukin-23 Receptor (IL23R)
Group 3 ILCs (ILC3) reinforce the epithelial barrier and maintain homeostasis with gut microbiota
It has been found that MHC II-expressing CCR6 + type 3 ILCs control intestinal homeostasis by inducing apoptotic cell death and deleting the activation of commensal bacterial-specific T cells
Candidatus Savagella (Segmented filamentous bacteria/SFB) colonization in mice activates innate lymphoid cells (ILC3) to secrete Interleukin-22 (IL-22) that induces serum amyloid A protein 1 and 2, production to promote local Interleukin-17A (IL-17A) responses
MHC II + type 3 ILC could represent a new therapeutic target to control pathological CD4+ T cell responses in chronic inflammatory diseases
Hepworth et al. (2013) showed that ILC3s could process as well as present antigen to T-cells.
RAR-related orphan receptor gamma/t (ROR-gamma/t) Isoform 2 (NR1F3) ILCs (ROR-gamma/t + ILC) are the major source of intestinal Interleukin-22 (IL-22) that is dependent on Aryl Hydrocarbon Receptor (AhR)
Qiu et al. 2012 Immunity. 36: 92-104
Group 3 ILCs (ILC3) express the Th17 / Th22 cell master regulator RAR-related orphan receptor gamma/t (ROR-gamma/t) (NR1F3) and their effector cytokines Interleukin-22 / IL-22 Receptor (IL-22R), Interleukin-17A (IL-17A), and Interleukin-17F (IL-17F)
The infographic was created using AI
A critical factor in the progression of these diseases is the dysregulation of innate lymphoid cells type 3 (ILC3), both in their numbers and functions.
Several diseases, including inflammatory bowel disease (IBD), human immunodeficiency virus (HIV), graft-versus-host disease (GVHD), and colorectal cancer (CRC), are affected by the loss of ILC3 homeostatic functions. These functions include antigen presentation and the production of interleukin-22 (IL-22). When these functions are compromised, the intestinal barrier fails, allowing antigens to translocate and sensitize the immune system. This sensitization leads to abnormal T cell responses.
Dysregulated IL-22 signaling can result in epithelial hyperplasia, which, when coupled with chronic inflammation, may lead to colorectal cancer. Therefore, restoring ILC3 functions could be a potential therapeutic approach for treating these disorders.
NCR-expressing ILC3 (NCR+ ILC3) exhibit a degree of functional and transcriptional plasticity. In an inflammatory cytokine environment, these cells can lose RORγt expression and transform into ILC1-like Bex-ILC3. This phenotype is associated with the production of proinflammatory cytokines, such as interferon-gamma (IFN-γ), which have been implicated in driving intestinal pathology and tissue damage in IBD.
Therapeutic interventions that suppress inflammatory ILC3 may offer a novel strategy to promote the resolution of disease in various intestinal disorders. By targeting the dysregulated functions of ILC3, it may be possible to alleviate the symptoms and progression of these conditions.
see also:
Group 3 ILCs (ILC3) & Gut microbiota
Group 3 ILCs (ILC3) & RAR-related orphan receptor gamma/t (ROR-gamma/t) (NR1F3)