Authors:

Seata Beptuła-Karan

Veterinary Center of the Nicolaus Copernicus University, Torun, Poland.

Abstract:

Recently, a class of immune cells known as innate lymphoid cells (ILCs) has been identified. ILCs are capable of maintaining homeostasis and defending humans and other mammals against infections and illnesses. In light of this, studies on ILC are still being conducted to learn more about the biology of these cells and how they function in the human body. Since ILCs are a diverse subset of immune cells, it is critical that the medical community stays up to date on the most recent findings about the roles played by ILC families in a number of disease states, including the development of cancer, metabolic disorders, and inflammation. Our understanding of ILC populations’ roles and their involvement in various ailments will help us diagnose diseases more accurately and provide better patient care.

Keywords :
innate lymphoid cells, innate immunity, natural immunity cells.

Introduction :
Recently, innate lymphoid cells (ILCs) were identified as a component of natural immunity that can contribute to infections and infectious disorders as well as help keep organisms in a state of homeostasis [1–24]. The digestive, respiratory, and urogenital systems, in addition to the skin, adipose tissue, blood, and several internal organs, can all include innate lymphoid cells [24–27]. The ILC families were described by Adamiak et al as follows: ILC22 cells, which share characteristics with NK and LTi cells, ILC17 cells, which produce interleukin-17 (IL-17), ILC2 cells, which are natural T helper 2 (nTH2) cells, nuocytes, innate helper type 2 (IH2) cells, and MPP type 2 cells (multifocal progenitor type 2). The ability of ILCs to produce important transcription regulators and cytokines, as well as their origin, are two other wellknown and frequently used classification criteria [29, 30]. This classification, which is also shown in Table I, separates the cells into three groups. Group 1 (ILC-1) is made up of cells that are sensitive to IL-12, IL-15, and IL-18. These cells have the ability to release TNF or IFN-α or activate the transcription factor T-bet [23, 31]. Thymic stromal lymphopoietin (TSLP)-sensitive cells, IL25, IL-33, and other cytokinesis-sensitive cells comprise Group 2 (ILC-2). These cells have the ability to activate the trans-acting-cell-specific transcription factor GATA-3 and produce IL-5, IL-13, IL-4, and amphiregulin (Areg), a protein that is part of the epidermal growth factor family [23]. The cells that respond to IL-1α and IL-23 make up Group 3 (ILC-3). which release IL-17a, IL-22, granulocyte-macrophage colony-stimulating factor (GMCSF), and IFN-α and activate the ROR-t transcription factor [31]. The data that is now available indicates that there aren’t many ways to determine ILC cells, in part due to technological constraints. Examples of these methods include confocal microscopy, mass cytometry, and flow cytometry.

Th1 (T helper) cells, which can activate PMN and MN cells by enhancing their cytotoxicity, phagocytosis, and neutrophil extracellular trap (NET) formation, NK cells have cytotoxic capabilities similar to CD8+ T cells [41]. According to Wang et al. [46], there is a lymphocyte subset of NK-like B cells in the spleen and mesenteric lymph nodes. These cells differ from T and B cells in certain ways, and they have the ability to release IL-12 and IL-18 early in the infection process. Through the release of IL-12 and IL-18, these NK-like B cells were essential in the elimination of microbial infection [46]. In all of the tissues examined, Simoni et al. [33] were unable to find ILC1 cells; however, they did find intra-epithelial-ILC1-like cells, which are able to produce cytotoxic granules but do not express CD127. These cells, seen in both mucosal and non-mucosal diseased tissues, belong to a wider subset of NK cells. It’s possible that in their earlier research, the presence of T cells, DCs, ILC3 cells, HSC, and NK cells contaminated the sample, leading to an incorrect definition of ILC1 cells. These intra-epithelial-ILC1-like cells exhibited CD103, the transcription factor T-bet, and surface NK cell markers CD56, NKp46, CD94, 2B4, CD161, CD160, CD122, CD69, and CD49a, but not CD16 or CD127, in contrast to NK cells from the same region. Only the tonsils (5%) and colon tissue (25%) have these intraepithelial-ILC1-like cells in non-pathological tissues, according to Simoni et al. [33]. ILC-2 cells comprised 40% of the total ILC population in human skin, and their frequency in cord blood (2.7% cells) was higher than in adult blood (0.63% cells). According to their research, ILC-2 cells obtained from adult blood and stimulated with IL-33 have functional similarities with those seen in cord blood. ILC-2 and ILC-3 cells are attracted in diseased tissues, such as lung and colorectal tumours; nonetheless, NK and ILC1-like cells made up over 95% of the ILCs that infiltrated these inflamed tissues.

Native lymphoid cells and the development of cancer A major factor in the development and metastasis of cancer is the interaction of immune system (IS) cells, such as ILCs, and tumor-developing cells with the cells that comprise the tumour microenvironment. Tumour cells and IS cells can link through cytokines, adhesion molecules generated by the tumor’s growing cells as well as by the host cells; alternatively, metalloproteinases and so-called microbubbles may aid in the spread of the malignancy. The first reaction to the establishment of a tumour is the mobilisation of IS cells, which triggers cytotoxic mechanisms by producing cytokines, including antitumor ones, that cause cancer cells to undergo apoptosis and ultimately die. Cancer cells assume control of all microenvironment cells and start to create pro-tumor growth factors when they multiply and outcompete immune system cells [81–83]. T cells, including Th1, Th2, Treg, and Th17, B lymphocytes, NK cells, natural killer T (NKT) cells, DCs, macrophages (M1 and M2), myeloid-derived suppressor cells (MDSC), and the families of immune-like cells (ILCs), groups 1, 2, and 3, can be identified among the cells that form the tumor-forming microenvironment. Tissue healing during pregnancy as well as the advancement of the disease’s early stages may be aided by innate lymphoid cells, a source of cytokines. As a result, ILC families are crucial for both tissue continuity restoration and immunological activation. This unique property of ILC cells raises the possibility that they play a role in the formation and growth of tumours and may have an impact on the surrounding microenvironment of growing tumour cells. A number of components must work together to trigger an immune response in a tissue that has been damaged but is not infected, including DCs, macrophages, epithelial cells with active inflammasomes, and dam-age-associated molecular pattern (DAMP). Intracellular proteinaceous complexes known as inflammatorysomes have the dual roles of stimulating the family of ILC cells and initiating a proinflammatory cascade that results in the creation of pro-caspase-1. Increased ILC cell activity can potentially promote the growth of tumours.

ILC-1 cells secrete IL-2, IL-12, IL-18, and IL-21 and exhibit cytotoxic activity that can inhibit the growth of tumours [89]. On the other hand, while tumours are developing, NK cells that are part of the ILC-1 group may exhibit an increase in the expression of receptors like CD158 that can inhibit antitumor receptors while decreasing the expression of receptors like CD16, CD69, and CD161 that are important for antitumor activity [89]. This illness causes an imbalance in homeostasis and immunosuppression, which in turn causes a reduction in the blood’s supply of natural killer cells and ultimately accelerates the growth of cancer. On the other hand, DCs in the tumour microenvironment have a positive feedback effect on NK cells. This is because DCs with expertise in antigen presentation and immune response activation can help NK cells produce more cytokines and increase their cytotoxicity against tumour cells. Additionally, by enhancing DCs’ capacity to generate pro-inflammatory cytokines and stimulate T-helper (Th1) and T-cytotoxic (Tc) lymphocytes against tumour cells, NK cells “assist” in the activation of DCs [31]. New information about the possible contribution of innate-CD8+ T cells, also known as NK-like CD8+ cells, to the physicopathological advancement of cancer is offered by Barbarin et al. They note both the potential role of innate-CD8+ in solid tumours and chronic myeloid leukaemia, a myelo-proliferative condition regulated by the immune system. T cells’ vulnerability to tumour immune subversion and their role in controlling cancer illness. “Immune checkpoints” regulate innate-CD8+ T cells during tumour progression [90]. Additionally, it has been demonstrated that DC-activated NK cells may produce IL-12p70, a cytokine that can trigger a Th1 and Tc cell response and is resistant to inhibitory drugs, up to 100 times more efficiently [31]. Clinical investigations showing the great efficacy of combination therapy with NK and DCs in cutaneous melanoma have also confirmed these findings [31]

IFN-ε can stimulate Tc and NK cells [91] and prevent the proliferation of tumour cells and angiogenesis. It should be highlighted, nonetheless, that IFN- may also have negative effects, as IFN-produced by ILC-1 cells early in the immune response might induce tumour growth [95]. IFN-⁧ has been shown to have a negative impact on human melanoma cell culture in vitro, leading to an aggressive phenotype and tumour formation [96]. The differences in NK cell distribution in cancer tissues are described by Carrega et al. The presence of NK cells was compared between neoplastic and comparable healthy tissues from a variety of human organs, including the kidney, lung, colon, stomach, breast, and adrenal gland. Only in the group with lung and breast cancer were statistically significant differences found. The frequency of NK cells is larger in human colorectal tumours (73% of cells) than in non-pathological colon tissues (34% of cells), according to data published by Simoni et al. However, there were no appreciable differences in the frequency of intra-epithelial-ILC1-like cells. In lung cancer diseases, it was observed that whereas there were more intra-epithelial-ILC1-like cells in human lung tumours (8% cells) than in non-pathological lung tissues (1% cells), the number of NK cells in human lung tumours was lower (80% cells) than in non-pathological lung tissues (95% cells).

ILC-2 cells play a protective function against tumours by secreting IL-13 and amphiregulin, which have the ability to suppress type 1 responses associated with Th1 lymphocytes. A significant quantity of IL-5, which is required for the selective growth of eosinophils, can also be released by ILC-2 cells [78]. A better prognosis for patients is indicated by the presence of eosinophilic granulocytes in the developing tumour location, which includes the colon, oesophagus, nasal cavity, larynx, pulmonary adenocarcinoma, bladder, and prostate [97–99]. Furthermore, IL-5 generated by mouse ILC-2 cells impeded lung cancer spread and decreased tumour growth due to eosinophilia [98]. Furthermore, IL-5 generated by mouse ILC-2 cells slowed the growth of the tumour and prevented lung cancer from spreading. Additionally, it has been shown that IL-13, which is generated by IL-2 cells, is necessary for MDSC cell activation and can inhibit anti-tumor action by changing the growth factor-α (TGF-ε) that MDSC cells produce, which regulates the proliferation and differentiation of the majority of cell types. M2 macrophages can be stimulated by TGF-α and IL-13 to produce proangiogenic factors, which in turn promote the growth and metastasis of cancer cells. These factors include VEGF, matrix metallopeptidase (MMP-9), and the growth factors epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF-2) [100–102]. Therefore, it may be said that ILC-2 cells have a dual role in tumour formation. By generating type 2 cytokines, these cells can act in a way that promotes tumour growth. among them is IL-13, which encourages metastasis by stimulating the environment surrounding the developing tumour. ILC-2 cells are found in human colon tumours (1% cells) and non-pathological colon tissues (3% cells), as well as in human lung tumours (3% cells) and non-pathological lung tissues (2% cells), according to Simoni et al. [33]. Because ILC-3 cells can secrete IL-17, IL-22, or IL-23, which can induce chronic inflammation and raise the risk of colon cancer [104], it has been determined that these cells play a part in the formation of cancer. It’s possible that the IL-22 that ILC-3 cells release is what causes colorectal cancer to spread [11, 12]. In addition, IL-23 stimulates ILC-3 cells to promote the growth of tumours in the stomach, ovary, lung, and intestines. High IL-23 expression and IL-17 release are unfavourable prognostic variables in cancer because IL-17 promotes the growth of new blood vessels that supply the tumour by activating proangiogenic factor (VEGF) [107]. Furthermore, by activating STAT2 pathways, the IL-22 generated by ILC-3 cells promotes the growth of intestinal cancer cells and may result in persistent and recurring inflammatory conditions that may serve as a cancer risk factor [109]. There have been reports indicating ILC-3 cells have natural cytotoxic receptors (NCR) that are characteristic of natural killer (NK) cells, such as NKp46, NKp30, and NKp44. As a result, these cells can identify tumour cells or virus-infected cells [110–112]. Research has demonstrated that ILC-3 cells, through NKp44 receptor and cytokine Only a subset of ILC-3 cells in the immediate proximity of the tumour was found to have an active NKp44 receptor in lung cancer patients, but this receptor was dormant in healthy lung tissue [113]. After receiving hematopoietic stem cell transplantation (HSCT) for 12 weeks, patients with acute myeloid leukaemia (AML) have already shown signs of reconstructing their ILC-3 cell populations [114]. Patients undergoing allogeneic stem cell transplantation may suffer from tissue damage and graft-versus-host disease (GvHD), which can result in potentially fatal clinical signs include intestinal mucosal and skin inflammation. Additionally, it has been shown that the ILC-3 cell-synthesised IL-22 is a critical modulator of tissue susceptibility to GvHD and shields intestinal stem cells from harm. In order to verify this, researchers looked at AML patients, and they found a link between the lack of GvHD clinical symptoms and the existence of a sizable circulating population of NKp44+

Conclusions :
One type of immune cell that has multiple functions is the innate lymphoid cell. Their capacity to release immunoregulatory cytokines quickly enables them to support the early stages of the immune response following infection. Examining ILC cells’ function more closely could help establish new protocols that could result in better medical care, particularly in the area of immunity. It is constantly being researched how important ILC cells are to mammals’ immunity and homeostasis, including humans, in their role as “guardians.” A study that was released by the organisation Immunological Genome Consortium [37] defined the ILC code and detailed the transcriptional expression profiles of the ILC family in a variety of organs. They also made a recommendation regarding the other potential roles that ILCs may play in health protection, such as serving as a source of cells and markers for diagnosis, the existence of which can be utilised for both fundamental and diagnostic research. There are few studies that analyse every known ILC subset for a single tissue simultaneously, and it is difficult to compare human and mouse immunology. The first group to thoroughly examine the phenotypic characteristics of human ILCs was Simoni et al. [33]

Citation:

Seata Beptuła-Karan. The function of lymphoid cells in some health conditions, such as fibrosis, digestive problems, and cancer grow. Journal of Immunology 2024.