Type 3 innate lymphoid cells

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Schematic diagram of the development of ILCs, starting from the common lymphoid progenitor (CLP), mainly based on mouse differentiation pathways. ILC3s are shown in orange. ILC development 2 PNG.png
Schematic diagram of the development of ILCs, starting from the common lymphoid progenitor (CLP), mainly based on mouse differentiation pathways. ILC3s are shown in orange.

Type 3 innate lymphoid cells (ILC3) are immune cells from the lymphoid lineage that are part of the innate immune system. These cells participate in innate mechanisms on mucous membranes, contributing to tissue homeostasis, host-commensal mutualism and pathogen clearance. They are part of a heterogeneous group of innate lymphoid cells, which is traditionally divided into three subsets based on their expression of master transcription factors as well as secreted effector cytokines - ILC1, ILC2 and ILC3. [2]

Contents

Characterization

ILC 3 family can be divided into two subgroups based on their expression of natural cytotoxicity receptors (NCRs), designated NCR+ ILC3 and NCR− ILC3. These receptors are commonly found on natural killer cells and some subpopulations of innate and adaptive cells. They are involved in activation and cytotoxic activity of NK cells, including cells lysis and secretion of pro-inflammatory cytokines. [3] LTi cells (lymphoid tissue-inducing cells) are a subpopulation important in development of secondary lymphoid organs in embryogenesis. ILC3 cells produce cytokines typical for the population of Th17 helper lymphocytes. The characteristic feature of ILC3 is the expression of the RORγt transcription factor, which is needed for its development and expression of the chemokine receptor CCR6. [2] This group of ILC produces IL-17 (especially IL-17A) [4] and IL-22. [5] Both cytokines can be produced by ILC 3 simultaneously or separately, provided that when IL-22 is produced alone it is a matter of NCR+ ILC3. [5] ILC3 express IL-23R and the production of IL-17 and IL-22 is stimulated by IL-23 and IL-1β. [6] For ILC3, the expression of the transcription factor RORγt and partially also the Ahr (aryl hydrocarbon receptor) is typical since interactions of these two transcription factors cause the accumulation of ILC 3 and the production of IL-22 in the intestines. [7] There is high heterogeneity in surface markers of ILC3 cells, with tissue-speicifc populations that can differ in function based on context. [8] ILC3 cells have also phenotypic plasticity and have been observed to acquire ILC1-like phenotype under certain circumstances. [8] [9]

Function

ILC 3 represent a heterogenous population crucial for defense against extracellular parasites and maintenance of intestinal homeostasis. [2] They participate in effective antimicrobial defence through the production of IL-17 and IL-22. The role of IL-22 in humans and mice is somewhat different. In the murine model, IL-22 was found to play a role in improving the course of inflammatory bowel disease and epithelial restoration in the loss of the protective mucin barrier in the large intestine. [10] [11] However, in humans with inflammatory bowel disease, IL-22 has an effect on the pathology of the disease. [12] IL-22 is an important cytokine for maintaining intestinal homeostasis. The action of IL-22 helps enhance the defense of the surface of the intestinal mucosa by weakening the mucin layer [11] and its ability to produce antimicrobial agents, such as β-defensins, is a powerful mechanism that helps maintain intestinal homeostasis. [13] An increase in IL-22 levels together with increased β-defensin expression has been reported in inflammatory skin diseases such as psoriasis. IL-22, as well as IL-17, could thus be involved in the development of these skin diseases, since in humans without these problems IL-22 expression was not registered. [14] The effects of IL-17 and IL-22 can complement each other and stimulate an increased amount of antimicrobial peptides at the site of action. [13] Like ILC2, ILC 3 can express MHC II and be appropriating the function of antigen presenting cells. [15] However, ILCs lack the costimulatory receptors that are necessary for proper activation and initiation of the immune response. ILCs, on the contrary, may set the helper T lymphocytes in the state of anergy. In the case of ILC 3, the ability to express MHC II apparently serves to maintain tolerance to commensal bacteria in the intestine. They suppress the response of CD4 + T lymphocytes to harmless and beneficial intestinal bacteria. If this tolerance is not maintained, there can be a development of undesirable pathological conditions. [15] On the other hand, the action of IL-23 or IL-17 is not always beneficial. It causes some autoimmune diseases such as multiple sclerosis [16] or rheumatoid arthritis. [17] IL-17A specifically targets keratinocytes and is the major cytokine causing pathogenesis of skin psoriasis. [18] In addition, IL-17A is also expressed to an increasing extent in patients with inflammatory bowel disease. [19] ILC 3 may play a role already in the prenatal setting of the body's resistance to infections. LTi cells are important in the origin and development of secondary lymphoid organs. It has been found that differentiation and signalling of LTi cells are dependent on retinoic acid (a component of vitamin A). The uptake of retinoic acid in the diet by the mother directly affects the development of LTi cells and the size of the secondary lymphoid organs of the fetus, which may have an effect at its later age. [20]

ILC3 cells in disease

ILC3 cells act as sentinels of the gastrointestinal tract. They are involved in maintaining homeostasis and tolerance to commensals, but are also important in defense against invading pathogens. [21] Their transcriptional and cytokine profile is very similar to Th17 cells and ILC3s can also become pathogenic in certain circumstances, contributing to disease progression and inflammation. ILC3 have been linked to inflammatory bowel disease progression, which is an umbrella term describing chronic inflammatory conditions in the gastrointestinal tract, that have been linked to a plethora of factors including immune dysregulation and environmental cues, as well as genetic predisposition. Most well-known types of IBD are Crohn's disease and ulcerative colitis. Higher numbers of ILC3 cells have been detected in IBD patients’ colonic isolates. NCR− ILC3s have been shown to be pathogenic in the context of IBD, but not NCR+ ILC3s. [22] [23] Exact contribution of ILC3 subsets to the disease progression is not fully understood. Some studies show that Crohn's disease patients have decreased numbers of NCR+ ILC3s, which are key producers of IL-22. IL-22 is critical for intestinal epithelial barrier maintenance and integrity, and its decreased concentration could predispose to disruptions of epithelial barrier  functions. [23] Other studies however point to excessive ILC3 activation in both mouse models of IBD and human patients, where high levels of IL-22 were also detected. [24] Intestinal macrophages have been shown to accelerate intestinal inflammation through inducing IL-22 production by mucosal ILC3. [24] ILC3 have been observed to trans-differentiate into IFN-γ-producing ILC1-like cells via IL-23 and IL-12 signalling under certain circumstances, leading to chronic inflammation. [24] In cases of extensive invasion of pathogens to intestinal epithelium, overexpression of IL-22 and IL-17 by ILC3 might lead to excessive neutrophil influx, higher epithelial permeability and inflammation. [24]

ILC3 cells have in recent years also been linked to immune responses to fungal pathogen Candida albicans . [25] This opportunistic pathogen induces Th17 immune response. This is supported by the fact that ILC3 cells mirror the phenotype of Th17 cells, and a subset of ILC3 cells has also been recently observed to have potent antigen presenting properties. [26] ILC3s contribute in immune response to this pathogen by mediating the immune response via secretion of cytokines such as IL-17A. [25]

They have also been shown to play a role in lung health and lung disease progression, since the IL-17/IL-22 axis is crucial for proper lung functioning, and its disbalance can lead to pathology. [27] ILC2 group has been extensively studies in relation to lung health, since dysregulation in Th2 responses is linked to asthma and other pathologies This subset is also important for tissue repairs. ILC3s are, however, the most prevalent of the innate lymphoid cells populations in lung tissue. Balancing lung mucosal homeostasis and appropriate immune responses in infections is crucial. ILC3 cells are thought to play an important role in viral lung infections. In influenza infections, high levels of IL-17A have been detected shortly after infection, resulting in lung injury caused by extensive recruitments of neutrophils into the tissue. ILC3-derived IL-22 countered these effects, protecting the host tissues. IL-22 deficiency leads to extensive tissue damage. On the other hand, insufficient levels of IL-17A in influenza and bacterial co-infection resulted in secondary bacterial pneumonia. ILC3 cells likely play an important role in balancing out the immune response and protecting against secondary infections in disrupted mucosal epithelia, but in cases of dysregulation their activity can lead to tissue damage. [27]

In bacterial lung infections ILC3s are one of the source populations for IL-17, a key cytokine for bacterial clearance. Monocytes recruited to lungs in response to tissue damage and PAMPs have been observed to produce TNF, increasing the numbers of IL-17 secreting ILC3s, subsequently leading to neutrophil influx. ILC3-derived IL-22 promotes epithelial proliferation and production of anti-microbial molecules. [27]

ILC3 have also been implicated to play an important role in multiple sclerosis and the gut-brain axis. Multiple sclerosis is an autoimmune disorder driven by autoreactive T-cells, mainly Th1 and Th17 cells. Disruption in gut homeostasis is studied in relation to development of multiple sclerosis, as intestinal homeostasis appears to be essential for prevention of this disease. ILC3 cells have been implicated to have an important role in the pathogenesis of this disease, since they are a key population for gut homeostasis and tolerance. ILC3 cells express several surface receptors for diet-based compounds and microbial products alike, such as SCFA receptors. In multiple sclerosis patients or EAE mouse models, levels of SCFA in fecal matter are lowered, drawing a possible link between contents of gut lumen and ILC3 mediated homeostasis. Oral administration of SCFA has been shown to have beneficial effects in EAE in promoting Treg activity. [28]

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<span class="mw-page-title-main">Cell-mediated immunity</span> Immune response that does not involve antibodies

Cell-mediated immunity or cellular immunity is an immune response that does not involve antibodies. Rather, cell-mediated immunity is the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen.

Gut-associated lymphoid tissue (GALT) is a component of the mucosa-associated lymphoid tissue (MALT) which works in the immune system to protect the body from invasion in the gut.

<span class="mw-page-title-main">Interleukin 26</span>

Interleukin-26 (IL-26) is a protein that in humans is encoded by the IL26 gene.

<span class="mw-page-title-main">Interleukin 25</span> Cytokine that belongs to the IL-17 cytokine family

Interleukin-25 (IL-25) – also known as interleukin-17E (IL-17E) – is a protein that in humans is encoded by the IL25 gene on chromosome 14. IL-25 was discovered in 2001 and is made up of 177 amino acids.

<span class="mw-page-title-main">Interleukin 22</span> Protein, encoded in humans by IL22 gene

Interleukin-22 (IL-22) is protein that in humans is encoded by the IL22 gene.

Interleukin-22 receptor subunit alpha-2 (IL-22RA2), also known as interleukin-22 binding protein (IL-22BP) is a naturally secreted monomeric protein acting as an interleukin-22 (IL-22) antagonist with inhibitory effects on IL-22 activity in vivo. IL-22BP is in humans encoded by the IL22RA2 gene located on chromosome 6, and in mice is encoded by the il22ra2 gene located on chromosome 10. IL-22BP belongs to the class II cytokine receptor family and it is a soluble receptor homolog of IL-22R.

T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to actually inhibit Treg differentiation. However, Th17s are developmentally distinct from Th1 and Th2 lineages. Th17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces; such protective and non-pathogenic Th17 cells have been termed as Treg17 cells.

<span class="mw-page-title-main">RAR-related orphan receptor gamma</span> Cellular receptor

RAR-related orphan receptor gamma (RORγ) is a protein that in humans is encoded by the RORC gene. RORγ is a member of the nuclear receptor family of transcription factors. It is mainly expressed in immune cells and it also regulates circadian rhythms. It may be involved in the progression of certain types of cancer.

Gamma delta T cells are T cells that have a γδ T-cell receptor (TCR) on their surface. Most T cells are αβ T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, γδ T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells. Their highest abundance is in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

<span class="mw-page-title-main">Interleukin-17A</span> Protein-coding gene in the species Homo sapiens

Interleukin-17A is a protein that in humans is encoded by the IL17A gene. In rodents, IL-17A used to be referred to as CTLA8, after the similarity with a viral gene.

<span class="mw-page-title-main">Microbial symbiosis and immunity</span>

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<span class="mw-page-title-main">Mucosal immunology</span> Field of study

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Mucosal-associated invariant T cells make up a subset of T cells in the immune system that display innate, effector-like qualities. In humans, MAIT cells are found in the blood, liver, lungs, and mucosa, defending against microbial activity and infection. The MHC class I-like protein, MR1, is responsible for presenting bacterially-produced vitamin B2 and B9 metabolites to MAIT cells. After the presentation of foreign antigen by MR1, MAIT cells secrete pro-inflammatory cytokines and are capable of lysing bacterially-infected cells. MAIT cells can also be activated through MR1-independent signaling. In addition to possessing innate-like functions, this T cell subset supports the adaptive immune response and has a memory-like phenotype. Furthermore, MAIT cells are thought to play a role in autoimmune diseases, such as multiple sclerosis, arthritis and inflammatory bowel disease, although definitive evidence is yet to be published.

<span class="mw-page-title-main">Interleukin 23</span> Heterodimeric cytokine acting as mediator of inflammation

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<span class="mw-page-title-main">Intestinal mucosal barrier</span>

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<span class="mw-page-title-main">ILC2</span>

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<span class="mw-page-title-main">Interleukin 17F</span>

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T helper cell 22, also known as the Th22 cell, are a type of immune cell. Th22 are a derivative of naïve CD4+ T cells induced by the ligand activation of the transcription factor aryl hydrocarbon receptor (AhR), which uses environmental, metabolic, microbial, and dietary cues to control complex transcriptional programmes. Th22 cell’s function is mediated by its ligand specific cytokine interleukin-22 (IL-22).

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