Innate lymphoid cell
Innate lymphoid cells are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors. 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. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology, absence of rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.
Based on the difference in developmental pathways, phenotype, and signalling molecules produced, in 2013, ILCs were divided into three groups: 1, 2 and 3, however, after further investigation, they are now divided into five groups: NK cells, [|ILC1s], ILC2s, ILC3s, and lymphoid tissue inducer cells. 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. The dysregulation of ILCs can lead to immune [|pathology] such as allergy, bronchial asthma and autoimmune disease.
Classification
The development of ILCs is initiated in response to the presence of transcription factors that are switched on due to the presence of surrounding microenvironmental factors, such as: cytokines, notch ligands, and circadian rhythm. 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.| Stimuli | Tissue Signals | Cell | Mediators | Immune Function |
| Tumours Intracellular microbes | IL-12 IL-15 IL-1B | IFN- Granzymes Perforin | Type 1 immunity | |
| Large extracellular molecules | IL-25 IL-33 TSLP | IL-4, IL-5, IL-13, IL-9 AREG | Type 2 immunity | |
| Extracellular microbes | IL-1B IL-23 | IL-22, IL-17 GM-CSF Lymphotoxin | Type 3 immunity | |
| Mesenchymal organizer cells | IL-1B IL-23 IL-6 | RANK, TNF, Lymphotoxin IL-17, IL-22 | Formation of secondary lymphoid structures |
Group 1 ILCs
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 shared and unshared features, the classification of human ILC1s has been problematic. Both cell types produce IFN-γ as their principle cytokine and require the transcription factor T-bet to do so.
Both cells can also produce IFN-γ when the cytokines IL-15 or IL-12 are up-regulated in tissues after infection or injury, and secrete TGFβ1 in tandem with IFN-γ when stimulated. This drives gut epithelial and extra-cellular matrix remodelling. IL-18 co-stimulation also significantly increases IFN-γ levels. 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, further contributing to the inflammatory response, depending on their molecule expression.
There are 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 to be present in T-bet deficient hosts, but ILC1s are completely dependent on its presence. Development of NK cells is, however, completely dependent on the presence of the transcription factor Eomes, whereas ILC1s can develop independent of its presence. 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 -.
ILC1s and NK cells have some phenotypic markers in common, including: NK1.1 in mice, and NK cell receptors such as NKp44 and NKp46 in both humans and mice. They also have differences in phenotypic markers, including the expression of CD127 on 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. The relationship between the ILC1 and NK cell lineages still remains fuzzy due to a lack of these characteristic markers present on some NK/ILC1 cells in certain tissues, or after certain infection/inflammation events. This supports the tissue specific function theory. 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, a fundamental feature of NK cells.
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.
Group 2 ILCs
ILC2s are tissue resident and involved in the innate response to parasites, such as helminth infection, by helping repair tissue damage. They are abundant in tissues of the skin, lung, liver, and gut. 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. Due to their cytokine signature, they are considered the innate counterparts of Th2 cells.They express characteristic surface markers and receptors for chemokines, which are involved in the distribution of lymphoid cells to specific organ sites. In humans, ILC2s express CRTH2, KLRG1, SST2, CD161, and CD25. In mice, ILC2s express CD44, but not CD161.
ILC2s require IL-7 for their development, activating the fundamental transcription factors RORα and GATA3. GATA3 is also required for maintenance of ILC2 function, with GATA3 deprivation inhibiting the development and function of the cells.
Although considered homogenous, ILC2s can be classified into subpopulations of natural ILC2s, and inflammatory ILC2s, dependent on their responsiveness to IL-33 and IL-25. nILC2s are those responsive to IL-33 in tissues in a natural immune state, while iILC2s respond to IL-25 or the [|helminth parasite]. nILC2s express more Thy1 and ST2, and reduced KLRG1. iILC2s, express more KLRG1, and reduced Thy1 and ST2. In addition to these subpopulations, another population, named the ILC210 cell, is characterised by its ability to produce IL-10.
Group 3 ILCs
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. Human adult ILC3s, are primarily found in the lamina propria of the intestine, and the tonsils, however, they are also found in the spleen, endometrium, decidua, and skin.ILC3s are dependent on the transcription factor RORγt for their development and function. They express RORγt in response to IL- 1β and IL-23, or pathogenic signals. IL-22 is the principle cytokine produced by ILC3s and plays a fundamental role in maintaining intestinal homeostasis. However, ILC3s produce a variety of other cytokines, including IL-17, IL-22, IFN- γ, and GM-CSF, depending on the environmental stimuli.
There are two subsets of ILC3s, NCR- and NCR+ ILC3s, with the displayed NCR on mice ILC3s being NKp46, in comparison to NKp44 displayed on human ILC3s. NKp44+ ILC3s are highly enriched in the tonsils and intestines, as an exclusive source of IL-22. Some ILC3s can also express other NK cell markers, including NKp30 and CD56. NCR- ILC3s mainly produce IL-17A and IL-17F, and under certain circumstances, IL-22. NCR- ILC3s can differentiate into NCR+ upon increased expression levels of T-bet. Despite expressing NK cell markers, ILC3s differ greatly from NK cells, with different developmental pathways and effector functions.
Lymphoid Tissue inducer (LTi) cells
LTi cells are considered a separate lineage due to their unique developmental pathway, however, they are often considered to be part of the ILC3 group due to their 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, which they do through the action of lymphotoxin, a member of the TNF superfamily. They are critical during both 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. They have a pivotal role in primary and secondary lymphoid tissue organisation and in adult lymphoid tissue, regulating the adaptive immune response and maintaining secondary lymphoid tissue structures.Their production is stimulated by retinoic acid, CXCL13, RANK-L, and the cytokines IL-1B, IL-23, and IL-6. They express c- Kit, CCR6, CD25, CD127, and CD90, however, no NCRs. The expression of OX40L is another good marker for LTi cells in adult mice and humans. They can be either CD4+/-. Like ILC3s, upon activation, LTi cells mostly produce IL-17A, IL-17F, and IL-22. They are mediated by RANK, TNF, IL-17, and IL-22.
LTi cells induce the expression of AIRE, the autoimmune regulatory gene, by allowing development of embryonic thymic epithelial cells. They do this via lymphotoxin α4β7 and RANK-L signalling. LTi cells also allow the survival of memory CD4+ T cells, and therefore memory immune responses, within newly formed lymph nodes. They do this via the TNF superfamily members OX40L and CD30L, which signal to CD4+ T cells. This role could be used to prevent autoimmunity and to enhance memory responses after vaccination.