Innate lymphoid cell

Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). 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 (immune associated), 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 (due to the lack of the RAG gene), 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 (LTi) 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.

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 (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.

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 (NCRs) 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.