Innate lymphoid cell

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Innate lymphoid cells (ILCs) are a group of innate immune cells that are derived from common lymphoid progenitor (CLP) and belong to the lymphoid lineage. These cells are defined by absence of antigen specific B or T cell receptor because of the lack of recombination activating gene (RAG). ILCs do not express myeloid or dendritic cell markers.[1]

This relatively newly described group of cells has varying physiological functions; some functions are analogous to helper T cells, while the group also includes cytotoxic NK cells. Accordingly, they have an important role in protective immunity and the regulation of homeostasis and inflammation, so their dysregulation can lead to immune pathology such as allergy, bronchial asthma and autoimmune disease.[2] In addition, they can regulate adipose function and metabolic homeostasis, in part by eliciting beiging.[3]

Classification[edit]

ILCs can be divided based on the cytokines that they can produce, and the transcription factors that regulate their development and function. For each newly discovered branch of the ILC family, it will be important to determine whether a cell type represents a stable lineage or just a stage of differentiation or activation.[4] The emerging body of data about the transcription factors and cytokine signals that differentiate ILCs contributes to the evolving classification system used to identify ILCs.

In 2013 a nomenclature and classification system was proposed that divides the known ILCs into three groups.[5]

Group 1 ILCs[edit]

Group 1 ILCs constitutively express transcription factor T-bet and is able to produce Th1 cytokines (notably IFNγ and TNF) after stimulation with IL-12 or IL-18.

ILC1 cells comprise NK cells, CD127low CD103+ intraepithelial ILC1s and CD127high ILC1s.[6]

  • ILC1s are weakly cytotoxic cells closely related to Group 3 ILCs, from which they even appear to arise. ILC1s are analogous to Th1 cells and share the common transcription factor of T-bet.
  • Natural killer ('NK') cells are cytotoxic innate effector cells analogous to the cytotoxic T cells of the adaptive immune system.[7] They are distributed throughout the blood, organs, and lymphoid tissue and make up around 15% of the peripheral blood lymphocytes. NK cells play a role in tumor surveillance and the rapid elimination of virus-infected cells. They do not require the missing “self” signal of MHC Class I and can recognize stressed cells in the absence of antibodies, allowing them to react much more quickly than the adaptive immune system. NK cells, discovered in 1975, are the prototypical innate lymphoid cell, and have been described as large granular lymphocytes that lack the T cell receptor.[8]

Group 2 ILCs[edit]

Group 2 ILCs can produce type 2 cytokines (e.g. IL-4, IL-5, IL-9, IL-13).

ILC2s (also termed natural helper cells, nuocytes, or innate helper 2 cells[9] ) play the crucial role of secreting type 2 cytokines in response to helminth infection. They have also been implicated in the development of allergic lung inflammation.[10] They express characteristic surface markers and receptors for chemokines, which are involved in distribution of lymphoid cells to specific organ sites. They require IL-7 for their development, which activates two transcription factors (both required by these cells)—RORα and GATA3. After stimulation with Th2 polarising cytokines (e.g. IL-25, IL-33, TSLP) ILC2s start to produce IL-5, IL-13, IL-9, IL-4. ILC2s are critical for primary responses to local Th2 antigens e.g. helminths and viruses and that is why ILC2s are abundant in tissues of skin,[11] lungs, livers and gut.[12]

In mice, ILC2s can regulate adipose function and metabolic homeostasis in part via production of enkephalin peptides that elicit beiging.[3]

Group 3 ILCs[edit]

Group 3 ILCs are defined by their capacity to produce cytokines IL-17A and/or IL-22. They are the innate counterpart to Th17 cells, and share the common transcription factor of RORγt. They comprise ILC3s and lymphoid tissue-inducer (LTi) cells:

  • ILC3s are a lymphoid cell population that can produce IL-22 and expresses NKp46 (an NK cell activating receptor). Nevertheless, ILC3s differ from NK cells, as they are dependent on transcription factor RORγt, they lack cytotoxic effectors (perforin, granzymes and death receptors) and they do not produce IFNγ or TNF. They are found mainly in mucosal tissues and particularly in the intestinal tract.
  • Lymphoid tissue inducer ('LTi') cells Lymphoid tissue inducer cells are a subset of innate lymphoid cells belonging to lymphoid lineage of hematopoetic origin. They are represented by embryonic lymhoid tissue inducer cells, which have the pivotal role in primary and secondary lymphoid tissue organization, and adult lymphoid tissue inducer cells, regulating adaptive immune response and maintaining secondary lymhoid tissue structure.[13]

Characterization of LTi cells[edit]

LTi are cells positive for IL7+CD45+CD4+ and negative for CD3 marker expressing LTαβ.[14][15][16] Additionally, they express TNF-related activation-induced chemokine (TRANCE), Tumor Necrosis Factor Superfamily Member 14 (TNFSF14, also known as LIGHT) and Tumor Necrosis Factor Alpha (TNFα), which are all ligands of the tumor necrosis factor (TNF) family. They also express chemokine receptors, such as C-X-C chemokine receptor type 5 (CXCR5), C-X-C chemokine receptor type 7 (CXCR7), and adhesion molecules Very Late Antigen-4 (VLA-4, also known as Integrin α4β1), Integrin α4β7 and Intercellular Adhesion Molecule 1 (ICAM-1). Furthermore, LTis are positive for CD25, CD44, CD90, CD117, CD122, CD132 markers.[13][17]

Generation of LTi cells[edit]

LTi cells are the very earliest hematopoietic cells colonizing lymphoid node anlagen, fetal spleen and intestine induced Peyer’s patches and the nasal associated lymphoid tissue.[18][19] They are derived from IL-7Rα+ fetal liver precursor cells. LTi cells induce the development of secondary lymphoid organ anlagen through interaction with LTβR being expressed by mesenchymal cells. The presence of the transcription factor Ikaros and the protein Id2 (member of the Id family) is a prerequisite for differentiation of progenitor cells into CD45+CD4+CD3- LTi cells.[20] Another molecule required for the generation of LTi is the nuclear retinoic acid related-orphan receptor RORγt.[21] TRANCE-R triggering leads to enhanced expression of LTαβ on LTi cells. Signaling via the IL-7R or via the TRANCE-R are important for intiatiot of surface LTαβ expression in LTi cells.[22]

Development[edit]

CLPs, or common lymphoid precursors have the ability to differentiate into a number of different cell types including T cells, B cells, and ILCs, depending on the cellular signals present. With the exception of NK cells, all ILCs require IL-7 signaling for survival. Transcriptional repressor ID2 appears to antagonize B and T cell differentiation, yielding an ID2-dependent precursor that can further differentiate with lineage-specific transcription factors. There is evidence that the different branches of ILCs share a common precursor.[23] Notch signaling may also be involved in the initial differentiation to a common ILC precursor. The development of ILCs is not completely understood.[24] ILC3s may be necessary precursors to ILC1s.[25]

Function[edit]

ILCs are a multifunctional group of cells. Their ability to rapidly secrete immunoregulatory cytokines allows them to contribute early on in immune responses to infection. They often reside at mucosal surfaces, where they are exposed to infectious agents in the environment.

Helminth infection[edit]

ILC2 cells play a crucial role in the protection against helminthic infection. They 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. They also secrete Amphiregulin, a member of the epidermal growth factor family, that stimulates tissue repair. This can function to enhance the barrier function of the epithelium and slow pathogen entry.[26]

Enteric pathogens[edit]

In the environment of intestinal tract, ILC3s have a crucial role in mediating the balance between symbiotic microbiota and the intestinal immune system. In response to inflammatory signals from the dendridic cells and gut epithelium, they produce IL-22 which increase the production of antimicrobial peptides and defensins. ILC3s also assist in immune responses to extracellular bacteria by maintaining the homeostasis of epithelia. Therefore, when malfunction appears, these cells may participate in the development of inflammatory bowel diseases (IBD).[2]

Tumor surveillance[edit]

Different groups of Innate lymphoid cells have ability to influence tumorigenesis in several ways.

ILC1 are the major population of ILC with anti-tumorigenic potential.[27] The best explored ILC1 are NK cells. Their function is regulated by signals from stimulatory and inhibitory receptors. NK cells have ability to recognize missing MHC class I on tumor cell. In this way, they act in a complementary manner with the cytotoxic T cells that recognize and kill tumor cells which present a foreign antigen on MHC class I.[28][29] NK cells express a number of cell surface activating NK cell receptors with specificity for stress induced ligands overexpressed on tumor cell. In humans, receptor NKG2D[30] recognize ULBP1-6 and MICA, MICB and RAET1E, whereas in mice it binds RAE1 family molecules, H60 family molecules and MULT1 protein. Another family of activating NK cell receptors are NCRs (natural cytotoxicity receptors), DNAM1 (DNAX Accessory Molecule-1 CD266) and CD16 (mediate ADCC after binding of tumor specific antibody on tumor antigen).

ILC1 influence tumor microenvironment by production of several cytokines e.g. IFNg and TNFa which at the beginning of immune response polarize other immune cells into inflammatory phenotype, e.g. M1 macrophages. ILC1 also recruit DC and cytotoxic T cells.[31] On the other hand, IFN g and TNF a play important role in induction of immunosuppressive phenotype of immune cells or MDSC, production of anti-inflammatory cytokines and formation of metastases.[32][33]

Other ILC populations also influence tumor microenvironment.

ILC2 produce cytokines that promote anti-inflammatory immune response e.g. IL-13, IL-4, Amphiregulin.[34] However, in some settings ILC2 produce IL-5 and promote cytotoxic response of eosinophils and antitumor response and metastasis suppression.[35]

ILC3 are involved in inflammation-related tumorigenesis by production of IL-17, IL-22, IL-23 cytokines. This microenvironment leads to tumor development and progression and contribute for better survival of cancer cells.[36]

Metabolism[edit]

Research identified ILC2s in adipose tissue as a factor in the development of obesity in mice. ILC2s are critical in energy homeostasis by producing methionine-enkephalin peptides in response to IL-33. This production promotes the emergence of beige adipocytes in white adipose tissue. The process of beiging leads to increased energy expenditure and decreased adiposity.[3]

Pathology[edit]

Allergy and asthma[edit]

ILC2s play a variety of roles in allergy.[10] Primarily, they provide a source of the type 2 cytokines that orchestrate the allergic immune response. They produce a profile of signals in response to pro-allergenic cytokines IL-25 and IL-33 that is similar to those produced in response to helminthic infection. Their contribution to this signaling appears to be comparable to that of T cells. In response to allergen exposure in the lungs, ILC2s produce IL-13, a necessary cytokine in the pathogenesis of allergic reactions. This response appears to be independent of T and B cells. Further, allergic responses that resemble asthma-like symptoms have been induced in mice that lack T and B cells using IL-33. It has also been found that ILC2s are present in higher concentrations in tissues where allergic symptoms are present, such as in the nasal polyps of patients with chronic rhinosinusitis and the skin from patients with atopic dermatitis.[37][38]

Autoimmune disease[edit]

NK cells express many cell-surface receptors that can be activating, inhibitory, adhesion, cytokine, or chemotactic. The integration of information collected through these numerous inputs allows NK cells to maintain self-tolerance and recognize self-cell stress signals.[39] If the nuanced, dynamic regulation of NK cell activation becomes unbalanced in favor of attacking self cells, autoimmune disease pathology. NK cell dysregulation has been implicated in a number of autoimmune disorders including multiple sclerosis, systemic lupus erythematosus, and type I diabetes mellitus.[40]

Innate or adaptive[edit]

Historically, the distinction between the innate and adaptive immune system focused on the innate system’s nonspecific nature and lack of memory.[4] As information has emerged about the functions of NK cells and other ILCs as effectors and orchestrators of the adaptive immune response, this distinction has become less clear. Some researchers suggest that the definition should focus more on the germline-coding of receptors in the innate immune system versus the rearranged receptors of the adaptive immune system.[39]

References[edit]

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See also[edit]