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Hi there, my name is Mary Kelly, I am from Imperial College London, and I am edditing the Innate lymphoid cell article as part of an assignment. I will be working on this until 17/04/2020. Many Thanks, Mary Kelly

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Innate Lymphoid Cell (Draft)

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Innate lymphoid cells are the most recently discovered family of innate immune cells, derived from common lymphoid progenitor (CLPs).[1] In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells.

Characteristics allowing their differentiation from other immune cells include the absence of regular lymphoid morphology, rearranged antigen receptors (due to lack of RAG gene), and phenotypic markers usually present on myeloid and dendritic cells.

ILCs are primarily tissue resident cells, found in both lymphoid and non- lymphoid tissues, and rarely in the peripheral blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis.

Based on the difference in developmental pathways, phenotype, and signalling molecules produced, in 2013, they were divided into three groups: 1, 2 and 3, however, after further investigation, we now appreciate five distinct subsets within these groups: NK cells, ILC1s, ILC2s, ILC3s, and LTi cells.[2]

ILCs are implicated in multiple physiological functions, including tissue homeostasis, morphogenesis, metabolism, repair, and regeneration. Many of their roles are similar to T cells, therefore they have been suggested to be the innate counterparts of T cells.[3]

Classification

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The development of ILCs is initiated in response to the presence of transcription factors that are switched on due the presence of surrounding microenvironmental factors, such as: cytokines, notch ligands, and circadian rhythm (inbuilt behavioural changes following a daily cycle). Once matured, the ILCs release cytokines. The classification of ILCs is therefore based on the differences in the transcription factor and cytokine profiles associated with the development and function of the different ILC subtypes.[4]

Group 1 ILCs

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ILC1 and NK cell lineages diverge early in their developmental pathways and can be discriminated by their difference in dependence on transcription factors, their cytotoxicity, and their resident marker expression.

NK cells are cytotoxic cells, circulating in the bloodstream, killing virus-infected, and tumor cells. ILC1s, are non- cytotoxic or weakly cytotoxic, tissue resident cells, functioning in the defence against infections with viruses and certain bacteria.

Due to ILC1s and NK cells having both common and uncommon features, the classification of ILC1s has been problematic. Both cell types produce IFN-γ as their principle cytokine and require the transcription factor T-bet to do so.[5] The cells can also produce IFN-γ in response to the cytokines IL-15 or IL-12 up-regulated in tissues after infection or injury. IL-18 costimulation significantly increases IFN-γ levels.[6] The release of IFN-γ stimulates macrophages, and other mononuclear phagocytes, to induce an antimicrobial effect to eradicate intracellular infections. Oxygen radicals produced by both cell types also aid in the eradication of infection. ILC1s and NK cells can also produce TNF- α, depending on their molecule expression.

ILC1s and NK cells have some phenotypic markers in common, including: NK1.1 in mice, and NCRs such as NKp44 and NKp46, in both humans and mice.[1] [5] They also have differences in phenotypic markers, including expression of CD127 in human ILC1s, which is not present on all NK cells. In addition, NKp80, a marker for human NK cells, is not expressed on ILC1s. In mice, CD200R has been shown to distinguish NK cells from ILC1s.[7] The relationship between the ILC1 and NK cell lineages still remains fuzzy due to a lack of these characteristic markers present on NK/ILC1 cells in certain tissues, or after certain infection/inflammation events, supporting the tissue specific function theory.[1] For example, CD127, although expressed by the majority of ILC1s, is absent from the salivary gland resident ILC1s, which also have the ability to express Eomes.[8]

There are also differences in dependence on transcription factors between NK cells and ILC1s. Although both cell types use T-bet for development, NK cells have been found present in T-bet- deficient hosts, however, ILC1s are completely dependent on its presence.[5] Development of NK cells are however completely dependent on the present of the transcription factor Eomes, whereas, ILC1s can develop in its presence or absence.[5] This means, Eomes can generally be used as a marker for NK cells, suggesting that mature NK cells are Tbet + Eomes +, and ILC1 are Tbet + Eomes -. [9]

Due to the production of granzymes and perforin, NK cells are considered the innate counterparts of cytotoxic CD8+ T cells, whereas, ILC1s, are considered the innate counterpart of Th1 cells, due to the sole production of IFN-γ, without cytotoxic activity.[10]

Group 2 ILCs

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ILC2s are tissue resident and involved in the innate response to parasites such as the helminth infection, by helping repair tissue damage, therefore they are abundant in tissues of the skin,[11][12] lung, liver, and gut.[5] [13] They are characterised by the production of amphiregulin, and type 2 cytokines, including IL-4, IL-5, and IL-13, in response to IL-25, TSLP, and IL-33.[5] Due to their cytokine signature, they are considered the innate counterparts of Th2 cells.


ILC2s require IL-7 for their development, activating the transcription factors RORγt and GATA3 required development of the cells.[14] GATA3 is also required for maintenance of function, and GATA3 deprivation inhibits the development and function of the cells.

In humans, ILC2s express CRTH2, KLRG1, SST2, CD161, and CD25. [3] In mice, ILC2s express CD44, but not CD161. [3]

Although considered homogenous, ILC2s can be classified into subpopulations of natural ILC2s (nILC2s), and inflammatory ILC2s (iILC2s), dependent on their responsiveness to IL-33 and IL-25. [3] nILC2s are those responsive to IL-33 in tissue in a natural immune state, where as iILC2s, are those that responds to IL-25 or the helminth parasite.[3] nILC2s express more Thy1, and ST2, and reduced KLRG1.[3] iILC2s, express more KLRG1, and reduced Thy1 and ST2.[3] In addition to these subpopulations, another population named the ILC210 cells, are characterised by their ability to produce IL-10.[3]

Group 3 ILCs

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ILC3s are involved in the innate immune response to extracellular bacteria and fungi. They play a key role in homeostasis of the intestinal bacteria, and in regulating Th17 cell responses. [15]

Human adult ILC3s, are primarily found in the lamina propria of the intestine, and the tonsils, however, also in the spleen, endometrium, decidua, and skin.[16]

ILC3s are dependent on the transcription factor RORγt for their development and function.[17] They express RORγt in response to IL- 1B, and IL-23, or pathogenic signals.[18] IL-22 is the principle cytokine produced by ILC3s and is used to maintain the intestinal homeostasis. However, they produce a variety of other cytokines including: IL-17, IL-22, IFN- gamma, and GM-CSF, depending on the environmental stimulus.[19]

There are two subsets of ILC3s, NCR- and NCR+ ILC3s, with the NCR in mice being NKp46, and NKp44 in humans.[19] NKp44+ ILC3s are highly enriched in the tonsils and intestines, as an exclusive source of IL-22.[19] Some ILC3s can also express other NK cell markers, including NKp30, and CD56. [20] NCR- ILC3s produce mainly IL-17A, and IL-17F, and under certain circumstances, IL-22.[21] NCR- ILC3s can differentiate into NCR+ upon increased levels of T-bet.[4]

Despite expressing NK cell markers, they differ from NK cells as they lack common characteristics of NK cell such as: perforin and granzyme production, production of IFN gamma, and expression of death receptors.

LAST PARAGRAPH FROM ILC3 SECTION CAN STAY

LTi Cells

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LTi cells are considered a separate lineage due to their unique developmental pathway, however, they are often considered part of the ILC3 group as they have many similar characteristics. Like ILC3s, LTi cells are dependent on RORγt. They are involved in the formation of secondary lymph nodes, and Peyer’s patches, by promoting lymphoid tissue development, through the action of lymphotoxin.[5] They are critical during the embryonic and adult stages of development of the immune system, and therefore LTi cells are present in organs and tissues early during embryonal development.[5]

Their production is stimulated upon retinoic acid, CXCL13, RANK-L, and the cytokines: IL-1B, IL-23, and IL-6.[22] They express c- Kit, CCR6, CD25, CD127, and CD90, however, no NCRs.[5] The expression of OX40L is another good marker for LTi cells in adult mice and humans.[23] They can be CD4+/-. Like ILC3s, upon activation, LTi cells mostly produce IL-17A, IL-17F, and IL-22.[21] They are mediated by RANK, TNF, IL-17, and IL-22.

LTi cells induce the expression of AIRE, the autoimmune regulatory gene, by developing embryonic thymic epithelial cells. [23] They do this via lymphotoxin alpha1beta2 and RANKL signalling. [23]

LTi cells also allow the survival of memory CD4+ T cells, and therefore memory immune responses, within newly formed lymph nodes.[23] They do this via the TNF superfamily members OX40L and CD30L, which signal to the CD4+ T cells.[23] This role could be used to prevent autoimmunity, and to enhance memory responses after vaccination.[23]

Despite the above classification, ILC subsets display a certain degree of plasticity, with the ability to change phenotypic and functional capacities. This is in response to polarizing signals released in the resident tissue. Therefore, cytokine receptors, their transcription factors, and access of defined chromatin regions to the transcription factors, are required to allow the change.[5]

Development

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Our understanding of the pathways involved in the development of ILCs has only become clear in the last few years, with our knowledge mainly based on mouse pathways.[5]. ILCs are recombination activating gene (RAG)- independent, instead, they rely on cytokine signalling through the common cytokine- receptor gamma chain and the JAK3 kinase pathway for development. [24]

Early development

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ILCs are derived from CILPs (common innate lymphoid progenitors), which are derived from CLPs, which have the ability to differentiate into a number of different lymphoid cell types including T and B cells.[5] CILPs can then differentiate into NK cell precursors (NKP), or the more recently described CHILPs (common helper innate lymphoid progenitors). [5] CHILPs can then differentiate into LTiPs (lymphoid tissue inducer progenitors), and ILCPs (innate lymphoid cell precursors). The factors present in the microenvironment determine the progression of CLPs towards specific ILC groups, including notch ligands, cytokines, circadian rhythm, and the expression of transcription factors.

Identification of the ILC progenitor cell

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The development of CLPs to CILPs and on to ILCs requires the transcription factor ID2, to mediate suppression of the lymphoid cell fates generating T and B cells.[24] It does this via reducing activity of E-box transcription factors (E2A, E2-2, and HEB), critical in B and T cell development.[24] Initially it was assumed that Id2 was required in order for CLPs to differentiate into all ILC subsets, however, research showed that knock out of Id2 during CLP development, cripples the development of all ILC subsets other than NK cells. [25] Due to this realisation, a group of lineage negative cells (requirement of any true precursor cell), that were entirely dependent on the presence of Id2, and expressed other key ILC markers, were identified, with the phenotype: Lin-Id2+IL7Ra+CD25-α4β7+, which are now known as the common helper like innate lymphoid progenitors CHILPs.[25] They are named ‘common helper like’ due to their similarity to the T helper effector cell fates.

Transcription factor dependence

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Each stage of differentiation is dependent on expression of different transcription factors, including: NFIL3, TCF-1, ETS1, GATA3, PLZF, T-bet, Eomes, Runx3, RORα, Bcl11b, Gfi1, RORγt, and AhR. [5] The coordinated expression of these specific transcription factors activate or repress target genes critical in the differentiation of the lymphocyte subsets. [24] In particular, Nfil3, whose expression is regulated by cytokines, controls the differentiation of ILCs via the transcription factors Id2, RORγt, Eomes, and Tox.[26] This provides evidence for the tissue signals playing a key role in fate decisions into ILC lineages.

Origin and migration

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Studies suggest primary site of ILC development is in the liver in the foetus, and the bone marrow in adults, as this is where CLPs, NKPs, and CHILPs have been found.[24] The cells then exit and circulate in the blood until they reach their designated tissues, coded for by adhesion molecules and chemokines.[24] However, it has also been shown that the maturation of the ILCs can take place outside the primary lymphoid tissues, similar to the maturation of naïve T helper cells.

NK cell precursors, and ILC3 precursors have been found in the human tonsil, and foetal ILCPs present in the mouse intestine, accumulating in the Peyer’s Patches. [27] [28] Retinoic acid, produced by many cell types, such as nerve cells, dendritic cells, and stromal cells, favours the differentiation of ILC3s, rather than ILC2s, and it is required for their complete maturation. [24] In addition, AhR, which can be triggered through ligands produced after the catabolism food, is required for the maintenance of function and expression of intestinal ILC3s. [27]

Plasticity

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Our classification of ILCs into subsets provides a simplified framework, however, several studies suggest their development and phenotypic maintenance is much more complex, with a high level of plasticity between the subsets. Studies have confirmed the ability of some ILC subsets to convert into a different subset in the presence of specific cytokines.[10] This is also a common feature in T cells, and it is believed this plasticity is critical to allow our immune system to fine tune responses to so many different pathogens. [10] ILC plasticity occurs through exposure to polarising cytokines, however, it still remains unclear where these cytokines are produced and where the differentiation occurs in vivo.

The ILCs present in patients with chronic obstructive pulmonary disease (COPD) are a prototypical example of ILC plasticity. Studies in both humans and mice have shown lung resident ILC2s acquire an ILC1 phenotype during COPD, increasing IFN-γ secretion, and therefore inflammation. [29] Various triggers, including cigarette smoke, cause secretion of IL-12 and IL-18, causing the differentiation into ILC1s. GATA3 is down-regulated, and T-bet expression is up-regulated. [29] Patients therefore have a higher blood ILC1:ILC2 ratio, with the abundance of ILC1s present correlating with the severity of the disease.[29]

The ability of ILC3s to convert into ILC1-like cells has been shown in vitro, and in vivo. [30][31] When ILC3s are cultured with IL-2 and IL-15, it causes the up-regulation of T-bet, and the IL-12 receptor (IL-12R) β2, allowing conversion of ILC3s to ILC1s. In addition, studies suggest IL-23 can promote the conversion of ILC1s into ILC3s. [31]

There is increasing evidence indicating that ILC2s also have a certain degree of plasticity, with studies confirming their ability to convert into ILC1s and ILC3s upon exposure to specific environmental stimuli such as cytokines, or notch ligands. [32]

In certain environments, such as inflammation, chronic disease, or tumor microenvironments, activated NK cells can start to express CD49a, and CXCR6, common ILC1 markers, strengthening their plastic properties. [33] [34]

Function

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ILCs participate in our immune response to pathogens in all organs, in particular at mucosal surfaces. [10] They are key in the innate immune response due to their ability to rapidly secrete immunoregulatory cytokines, however, they also play a role in the shaping of the adaptive response by interacting with other immune cells. The microenvironment of the tissue they reside in determines and fine- tunes the expression of the diverse ILC profiles, facilitating their interaction in multiple effector functions.

The strategic positioning and deep rooting of ILCs within tissues allow them to maintain homeostasis, and therefore healthy tissue functioning. However, the ILCs also have detrimental roles in different mucosal sites.[35]

ILCs in helminth infection and tissue repair

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A fundamental property of type 2 immunity, and therefore ILC2 cells, is to deal with oversized organisms, that cannot be digested, such as the helminths.[36] In the intestine, in response to a helminth infection, epithelial cells secrete high levels of IL-25, activating ILC2 cells. ILC2s produce IL-13, which drives the differentiation of additional epithelial cells, via Notch signalling pathways. This instruction allows the tissue to be remodelled to allow for the expulsion of the helminth parasite, and other large pathogens.

ILC2s are a major early source of IL-13, which can activate T cells and induce physiological responses that will help expel a parasite. These physiological responses include stimulating goblet cell mucus secretion and contraction of smooth muscle. In addition, they secrete signals that recruit and activate mast cells and eosinophils, and which stimulate B cell proliferation. FROM WIKI ALREADY

The infection can lead to tissue damage, due to migration of the helminth. ILC2s have a key role in repairing the tissue damage after infection, by producing ligands such as AREG, for epithelial growth factor receptors, which facilitates differentiation of epithelial cells for tissue repair.[5] This can function to enhance the barrier function of the epithelium and slow pathogen entry.[37]

In multiple tissue niches, ILCs have a relationship with non- hematopoietic cells such as stromal cells. In the lung, ILC2s have a distinct localization to stromal cells, which release IL-33, and TSLP, promoting ILC2 homeostasis, in both the steady state, and in response to helminth infection, after the helminth has developed in the intestine, and migrated to the lung through the blood. [38]

Lung ILC2s are positioned close to blood vessels, to allow recruitment of eosinophils from the blood. In addition, they are also positioned within the airways, where potential pathogens may accumulate. This means they are in close contact with neuroendocrine cells, which activate ILC2s via the release of calcitonin gene-related peptide. [39] Other studies also confirm the regulation of ILC function via neuronal circuits.

ILC3s produce IL-22 in response to microbial infection, resulting in the epithelial cell production of anti-bacterial, and anti-viral proteins, via IFN-γ signalling. The IL-22 production also protects epithelial cells from apoptosis, via STAT3 signalling.[40]

In addition, ILC1s and ILC3s release oxygen radicals and lethally damaging enzymes in response to pathogenic infection, causing damage to the host tissue. The repair responses for the tissue are coordinated by the type 2 immune response, after the ILC3s and ILC1s have cleansed the tissue of microbes and debris. FIND REFERENCE.

During graft-versus-host disease (GVHD), which occurs after allogenic transplants, evidence suggests allogenic T cells attack and destroy ILC3s, resulting in reduced secretion of IL-22, and impaired epithelial cell functioning. This correlates with the role of ILC3s in tissue repair, and resolution of inflammation. [3]

NEED TO CHECK LAST FOUR PARAGRAPHS.

ILCs in the liver and metabolism

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All ILC subsets are present in the liver and regulate the immune response to protect the tissue from viral and bacterial infection.[41] ILC1s are the dominant ILC subset present in the liver. Their production of IFN – gamma promotes the survival of hepatocytes.[42] The production of IFN-γ by ILC1s is dependent on the expression of the NK cell receptor CD226.[42] CD226 expression is induced by IL-12, and extracellular ATP, and it upregulates the prosurvival molecules Bcl-2, and Bcl-xL, in hepatocytes.[42]

NK cells play a role in the immune response against viral hepatitis B and C, limiting liver fibrosis, and liver cancer. They eliminate hepatic cells in fibrotic liver via TRAIL and/or NKG2D. FIND REFERENCE.

ILCs play an important role in maintaining dietary stress, and metabolic homeostasis. The production of tryptophan metabolites causes the AhR transcription factor to induce IL-22 expression, maintaining the number of ILC3s present, and therefore intestinal homeostasis. [5] The vitamin A metabolite, retinoic acid, also upregulates the expression of IL-22, and therefore, the absence of the AhR signalling pathway, and of retinoic acid, results in reduced immunity to bacterial infections, such as gastrointestinal Citrobacter rodentium infection.[5] Retinoic acid also enhances the expression of gut- homing markers on ILC1s, and ILC3s. Dietary nutrient availability therefore modifies the ILC immune response to infection and inflammation, highlighting the importance of a balanced and healthy diet.

ILC2s support a type- 2 immune environment in the adipose tissue, via the production of IL-5, IL-4 and IL-13. This regulates adiposity, insulin resistance, and caloric expenditure.[5] Dysregulation of this causes persistent type 1 inflammation, leading to obesity. ILC2s promote the beiging of adipocytes, and therefore increased energy expenditure. Therefore, decreased responses of ILC2s in the tissue are a characteristic of obesity, as this interrupts their crucial role in energy homeostasis, resulting in reduced energy expenditure and increased adiposity. [43]

In addition to ILC2s, ILC1s contribute to the homeostasis of adipose tissue macrophages in both lean and obese conditions, making up 5-10% of the resident lymphocyte population, in human lean adipose depots.[1] A high fat diet increases ILC1 number, and activation of adipose tissue, increasing IFN-γ and TNF-α levels. ILC1s produce the macrophage chemoattractant CCL2, and therefore ILC1- macrophage signalling is a key regulator of adipose tissue.[44] This pathway could be a potential target for treating patients with liver disease.

ILCs in respiratory infection

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ILC2s promote epithelial and goblet cell proliferation, and therefore mucus production in the respiratory tract. These functions contribute to the restoration and maintenance of epithelial integrity. ILC2s provide a defence against helminth infections in the lung, via the production of Ahr, IL-9, and IL-13.[45] It is believed that these ILC2s originate in the intestine and migrate into the lung to fight the helminth infection.[46]

ILC1s and NK cells secrete IFN-γ in response to viral infection in the lungs, including rhinovirus, and respiratory syncytial virus (RSV).[3]

ILC3s are also implicated in lung infections, through the secretion of IL-17, and IL-22, for example in S. pneumonia infection. Further studies are required to decipher the role of ILCs in human respiratory infections.[47]

ILCs in cancer

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ILC3s have been reported to promote the formation of tertiary lymphoid structures in lung cancer, playing a protective role.[48]

Studies suggest, correlation between the presence of NK cells in the tumor microenvironment, and increased survival time of patients with lung cancer.[3] It is thought this is due to the increase in the inhibitory receptor NKG2A, and decrease in activatory receptors such as NKG2D, NKp80, and NKp30. The tumor microenvironment likely alters the phenotype of the NK cells to escape from NK cell mediated anti-tumor responses.[3]

Further research in human patients is required to further determine the role of ILCs in lung cancer.

ILCs in the intestinal mucosa

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Intestinal ILCs are exposed to dietary, microbial, and endogenous metabolites. ILC homing to the small intestine is mediated by α4β7 integrin, and the receptor CCR9. ILC2s express CCR9 in the bone marrow, so can directly home to the intestine, however, retinoic acid is required to allow CCR9 expression on ILC1s, and ILC3s. FIND REFERENCE FOR THIS.

ILCs facilitate maintenance of barrier integrity in the intestine, protecting from various bacteria and viral infections. ILC3s are the most abundant subset present in both the adult and foetal intestine.[49] The distribution of ILCs in the intestine changes during development, and they are unevenly distributed throughout the segments of the gastro-intestinal tract. This distribution to different niches within the intestine is mediated through distinct signalling cascades.[50] In humans, approximately 70% of the intestinal ILCs are NCR+, and 15% are NCR-.[51]

ILC3s directly interact with bacterial flora, creating a network between the microbiota, and the host, favouring homeostasis. ILC3s restrict colonization of multiple unbeneficial bacteria in the gut, via secretion of IL-22, stimulating epithelial cells to produce antimicrobial peptides.[52] The IL-22 production is induced due to the production of IL-23 and IL-1β by macrophages and DCs, and it promotes mucosal layer healing.[3] For example, IL-22 can promote repair of intestinal damage after chemotherapy or radiotherapy. ILC3s regulate the containment of commensal bacteria in the lumen, allowing it to be exposed to lamina propria phagocytes, leading to T cell priming. Although they can present antigens, via MHC class II receptors, ILCs lack co-stimulatory molecules, and therefore play a role in T cell anergy, promoting tolerance to beneficial commensals.[51] The relationship between ILC3s, and T cells in the gut is therefore crucial for maintaining homeostasis, as in the absence of ILC3s, there could be uncontrolled T cell activation. In addition, microbiota play a role in fine tuning IL-22 production by ILC3s, for example, segmented filamentous bacteria in the ileum regulate IL-22 production and allow differentiation of Th17 cells.[53][54]

ILC3s interact with the enteric nervous system to maintain intestinal homeostasis, as in response to bacteria, glial cells in the lamina propria secrete neurotrophic factors, which through the neuroregulatory receptor RET, induce IL-22 production by ILC3s.[55] Dendritic cells can also produce IL-23 during pathogen induced stress, also activating ILC3s allowing production of IL-22.

One of the mechanisms by which IL-22 regulates microbiota present in the gut is through the glycosylation patterns of epithelial cells.[56] IL-22, and lymphotoxin expression by ILC3s controls expression of fucosyltransferase 2, which allows fucosylation of epithelial cells, providing a nutrient source for the luminal bacteria.[56]

AHR ligands from diet or microbiota are recognised by immune cells, regulating ILC development and NK cell functions in the intestine. In response to tryptophan metabolites, AhR signalling maintains IL-22 expression and intestinal homeostasis.[5] Retinoic acid, produced by dendritic cells, promotes the expression of gut homing receptors on ILC1s, and ILC3s, and enhances ILC3 function, by upregulating RORγt, and IL-22.[5] There is also crosstalk between macrophages and ILC3s, via RORγt driven GM-CSF production, that is dependent on microbial signalling, and the production of IL-1β by macrophages.[51] A deficiency in dietary vitamin A results in abnormally small numbers of ILC3s, and therefore a reduction of IL-22 production, and higher susceptibility to infection. Conversely, retinoic acid suppresses ILC2 proliferation by down regulating IL-7Ra, and deprivation of vitamin A has been shown to enhance ILC2- mediated resistance to helminth infection in mice.[51]

ILC3s therefore form a network of interactions to maintain intestinal homeostasis, between the microbiome, intestinal epithelium, neuro-glial cells, and other immune cells.

LTi cells are present in Peyer’s Patches, and lymphoid follicles, interacting with B cells facilitating IgA production, which promotes host commensalism with the local microbiota.[57] NKp46+ ILC3s, are located close to the epithelium in the intestinal villi, mediating the host defence against pathogens.

ILC1s, and NK cells, produce IFN-γ to combat intracellular pathogens. Upon infection of C. dificile, ILC1s and ILC3s cooperate to combat the infection.[58]

ILC2s induce goblet cell differentiation, and mucus production in the intestine to protect from tissue damage upon parasitic infection.

In addition to ILCs in the intestinal mucosa, ILCs present in the oral mucosa protect against pathogenic infections, by maintaining the barrier function. The tonsils are coated by oral mucosa.

ILCs in skin repair

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Evidence shows ILC3s and ILC2s are recruited to the wounded dermis in both mice and humans, via epidermal Notch1 signalling.[51] The ILC3s secrete IL-17F, which plays a role in the immune, and epithelial cellular responses during wound healing, by recruiting macrophages to the site. The expression of TNF also plays a role in wound healing as it directs localization of ILC3s to the damaged skin epidermis.[51] In response to the release of IL-33 by the epidermis, ILC2s secrete high levels amphiregulin, a critical epidermal growth factor, therefore contributing to cutaneous wound healing.[51]

Pathology

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ILCs in asthma

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ILC2s have been confirmed to play a pathogenic role during lung inflammation. Epithelial cells in the lung express the cytokines IL-33 and IL-25, or TSLP, in response to various allergens, fungi, and viruses. These cytokines activate ILC2s, and therefore, an increased number of ILC2s, and type-2 cytokines (IL-4/5/13) are present in patients with allergic asthma.[3] They secrete IL-13, initiating allergic lung inflammation, as it promotes Th2 differentiation, orchestrating the allergic immune response.[59]

The production of IL-5 by ILC2s in the lung leads to eosinophil recruitment, and other cell populations are known to interact and shape the presence of lung ILC2s in airway inflammation in asthmatic patients – see image. (Do I need to explain this here or is image enough?)

In addition, they also promote proliferation of B cells. It is believed the increase in ILC2s present correlates with the severity of the disease, and evidence confirms some ‘allergen- experienced’ ILC2s persist after the resolution of the initial inflammation, portraying similarities to memory T cells. The presence of the ‘allergen- experienced’ ILC2s may be the reason asthmatic patients are often sensitised to various allergens.[51]

This allergic immune response appears to be independent of T and B cells, with evidence confirming that allergic responses that resembling asthma-like symptoms can be induced in mice that lack T and B cells, using IL-33. FROM WIKIPEDIA ALREADY.

How other ILCs impact asthma is less clear, however studies show correlation between the number of IL-17 producing ILC3s, and the severity of the disease. It has been shown in mice that NK cells and ILC1s inhibit ILC2 expansion due to the production of IFN-γ, and therefore may help control the disease. Further research in human patients is required to determine how the balance between the different subsets impacts asthma.[60]

ILCs in allergic rhinitis

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The frequency of ILC2s has also been found to be elevated in other tissues with allergic symptoms, such as the nasal polyps of patients with chronic rhinosinusitis, and in patients with aspirin exacerbated respiratory disease.[3] The concentration of ILC2s positively correlates with severity of the diseases.

ILC2s are activated due to presence of TSLP and IL-4, produced by epithelial cells and eosinophils respectively. They then produce IL-4, IL-5, and IL-13, further activating eosinophils, in a positive feedback loop, promoting inflammation. Disrupting this loop could be a potential therapy for rhinitis. NK cells appear to play a beneficial role, with fewer present in those with allergic rhinitis.[61]

ILCs in inflammatory bowel disease (IBD), and intestinal cancer

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Research suggests IL-17 producing NCR- ILC3s contribute to the pathophysiology of IBD due to their increased abundance in the intestine of patients with Crohn’s disease.[51] In addition, the number of ILC1s in the intestinal mucosa of patients with Crohn’s disease is increased from approximately 10% to 40% of the total ILCs present.[51] The increase in ILCs present correlates with the severity of the disease. Evidence suggests that the plasticity between ILC3s and ILC1s in the intestine is an important factor of Crohn’s disease, with ILC3s differentiating into ILC1s when exposed to IL-12 produced by dendritic cells.[51] However, IL-23, IL-1B and retinoic acid present in the intestine can drive the differentiation of ILC1s back to ILC3s.[51] Evidence also suggests the ability of ILC2s to acquire the pro-inflammatory phenotype, with ILC2s producing IFN-γ present in the intestine of patients with Crohn’s disease, in response to certain environmental factors such as cytokines.[51]

Patients with IBD have an increased risk of getting intestinal cancer due to chronic inflammation, when the ILC3s acquire the ILC1 pro-inflammatory phenotype during chronic inflammation. Since ILCs accumulate in the intestine of IBD patients, it is believed they may have a pro-tumorigenic role. Supporting this, studies show an increase in the amount of effector cytokines IL-23, IL-17, and IL-22, in the tumor microenvironment of intestinal cancer.[62][63][64]

NK cells secrete IFN-γ, which has anti-tumorigenic effects. Multiple studies show a decreased frequency of NK cells and IFN-γ present in the intestine or peripheral blood of patients with intestinal cancer.[65][66] Further studies are required to address their exact role in the intestinal cancer environment.

ILCs in liver cancer and obesity

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Hepatic ILC1s contribute to pathogenesis of chronic hepatitis B due to the production of IFN-γ, and TNF-α.

Disturbance of the epithelium lining the hepatic bile ducts is frequently observed in response to chronic liver inflammation, and increased proliferation of these ducts is associated with liver cancer.[41] Evidence suggests that the enhanced proliferation is triggered by IL-13, which is produced by IL-33 induced production of ILC2 cells. ILC2s have also been shown to enhance the progression of liver fibrosis, in turn promoting the development of liver cancer.[41]

The availability of specific dietary nutrients can affect ILC immune homeostasis by altering the energy stored in the adipose tissue. Adipose tissue maintains metabolism homeostasis and is now considered a fully immunocompetent organ. Malnutrition and gluttony can dysregulate ILC responses via changes in dietary nutrients, having direct effects on the energy stored in the adipose tissue.[1] Obesity is associated with changes of gastrointestinal flora, increased afflux of free fatty acids from adipose tissue into the liver and increased gut permeability.[1] The close anatomical proximity of the gastrointestinal tract and the liver means translocation of bacterial metabolites through the portal vein triggers inflammation, acting on innate immune cells, including ILC1s, therefore playing an important role in the activation of an inflammatory state in the liver. Therefore, inflammation associated with obesity can influence the progression of liver disease, due to the development of insulin resistance and metabolic dysregulation.[1] ILC1s as a key regulatory of adipose tissue inflammation, is therefore a potential therapeutic target for treating people with liver disease or metabolic syndrome.

ILC2s have also been identified in human and mouse white adipose tissue, contributing to the development of obesity. Decreased responses of ILC2s in the tissue are a characteristic of obesity, as this interrupts their crucial role in energy homeostasis, resulting in reduced energy expenditure and increased adiposity. FROM THE WIKIPEDIA PAGE ALREADY.

ILCs in skin inflammation

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The frequency of ILC2s is higher in the inflamed skin of patients with atopic dermatitis than in healthy patients.[51] The ILC2s from the skin of the patients had upregulation of the IL-25, IL-33, TSLP and PGD2 receptors, suggesting their role in the activation of ILC2s. Basophils and mast cells are also present in these skin lesions, producing IL-4, and PGD2, further activating ILC2s.

Psoriasis, another inflammatory skin disease, causes epidermal thickening, forming plaques which are mainly populated with T cells and dendritic cells. The T cells portray a type 1 immune response; however, the thickening and inflammation of the epidermis is thought to be caused by the production of IL-22, IL-17A, and IL-17F by T cells.[51] However, more recent data suggests that ILC3s infact produce a large number of these cytokines, with an increase in the number of ILC3s in the peripheral blood of patients with psoriasis.[51]













Link to classifcation section: helminth parasite

If want to add external links (see also only for wikipedia articles).

[edit]

NK cells 10 years on [5]

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