Innate lymphoid cell
Innate lymphoid cells (ILCs) are a group of innate immune cells 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.
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.
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. 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.
Group 1 ILCs
ILC1 cells comprise NK cells, CD127low CD103+ intraepithelial ILC1s and CD127high ILC1s.
- ILC1s are weakly cytotoxic cells closely related to ILC3s, 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. 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.
Group 2 ILCs
ILC2s (also termed natural helper cells, nuocytes, or innate helper 2 cells ) 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. 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. helmints and viruses and that is why ILC2s are abundant in tissues of skin, lungs, livers and gut.
Group 3 ILCs
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 are a subset of ILCs expressing molecules required for the development of lymphoid tissue. They are essential for development of lymphoid organs during embryogenesis and after birth regulate the architecture of lymphoid tissue. On top of that, they have been linked to the maintenance of T cell memory.
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. Notch signaling may also be involved in the initial differentiation to a common ILC precursor. The development of ILCs is not completely understood. ILC3s may be necessary precursors to ILC1s.
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.
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.
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).
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. 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. 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 recognize ULBP1-6 and MICA, MICB, 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. On the other hand IFN g and TNF a play important role in induction of immunosupressive phenotype of immune cells or MDSC, production of anti-inflammatory cytokines and formation of metastases.
Other ILC populatins also influence tumor microenvironment.
ILC2 produce cytokines that promote anti-inflammatory immune response e.g. IL-13, IL-4, Amphiregulin. However in some settings ILC2 produce IL-5 and promote cytotoxic response of eosinophils and antitumor response and metastasis suppression.
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.
Allergy and asthma
ILC2s play a variety of roles in allergy. 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.
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. 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.
Innate or adaptive
Historically, the distinction between the innate and adaptive immune system focused on the innate system’s nonspecific nature and lack of memory. 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 suggest the definition focus more on the germline-coding of receptors in the innate immune system versus the rearranged receptors of the adaptive immune system.
- Spits, Hergen; Cupedo, Tom (2012). "Innate lymphoid cells: emerging insights in development, lineage relationships, and function". Annual review of immunology. 30: 647–675. PMID 22224763. doi:10.1146/annurev-immunol-020711-075053.
- Walker, Jennifer A.; Jillian L. Barlow; Andrew N. J. McKenzie (February 2013). "Innate lymphoid cells—how did we miss them?". Nature Reviews Immunology. 13 (2): 75–87. ISSN 1474-1733. doi:10.1038/nri3349. Retrieved 2013-08-03.
- Lanier, Lewis L. (25 January 2013). "Shades of grey—the blurring view of innate and adaptive immunity". Nature Reviews Immunology. 13 (2): 73–74. doi:10.1038/nri3389.
- Spits, H. et al. Innate lymphoid cells — a proposal for uniform nomenclature. Nature Rev. Immunol. 13, 145–149 (2013)
- Juelke, Kerstin; Romagnani, Chiara (2016). "Differentiation of human innate lymphoid cells (ILCs)". Current opinion in immunology. 38: 75–85. doi:10.1016/j.coi.2015.11.005.
- Spits, Hergen; Artis, David; Colonna, Marco; Diefenbach, Andreas; Di Santo, James P.; Eberl, Gerard; Koyasu, Shigeo; Locksley, Richard M.; McKenzie, Andrew N. J.; Mebius, Reina E.; Powrie, Fiona; Vivier, Eric (February 2013). "Innate lymphoid cells—a proposal for uniform nomenclature". Nature Reviews. Immunology. 13 (2): 145–149. ISSN 1474-1741. doi:10.1038/nri3365.
- Spits, Hergen; Di Santo; James P (28 November 2010). "The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling". Nature Immunology. 12 (1): 21–27. PMID 21113163. doi:10.1038/ni.1962.
- Neill, Daniel R; See Heng Wong; Agustin Bellosi; Robin J Flynn; Maria Daly; Theresa K A Langford; Christine Bucks; Colleen M Kane; Padraic G Fallon; Richard Pannell; Helen E Jolin; Andrew N J McKenzie (2010-04-29). "Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity". Nature. 464 (7293): 1367–1370. ISSN 1476-4687. PMC . PMID 20200518. doi:10.1038/nature08900.
- Halim, Timotheus YF; et al. (2014). "Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation". Immunity. 40 (3): 425–435. doi:10.1016/j.immuni.2014.01.011.
- Roediger, Ben; et al. (2013). "Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells". Nature Immunology. 14 (6): 564–573.
- Neill, Daniel R.; et al. (2010). "Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity". Nature. 464 (7293): 1367–1370. PMC . PMID 20200518. doi:10.1038/nature08900.
- Withers, David R; Fabrina M Gaspal; Emma C Mackley; Clare L Marriott; Ewan A Ross; Guillaume E Desanti; Natalie A Roberts; Andrea J White; Adriana Flores-Langarica; Fiona M McConnell; Graham Anderson; Peter J L Lane (2012-09-01). "Cutting edge: lymphoid tissue inducer cells maintain memory CD4 T cells within secondary lymphoid tissue". Journal of immunology (Baltimore, Md.: 1950). 189 (5): 2094–2098. ISSN 1550-6606. doi:10.4049/jimmunol.1201639.
- Walker, Jennifer A.; Jillian L. Barlow; Andrew N. J. McKenzie (February 2013). "Innate lymphoid cells — how did we miss them?". Nature Reviews Immunology. 13 (2): 75–87. ISSN 1474-1733. doi:10.1038/nri3349. Retrieved 2013-08-03.
- Leavy, Olive (25 January 2013). "Innate-like lymphocytes: Will the real ILC1 please stand up?". Nature Reviews Immunology. 13 (2): 67–67. doi:10.1038/nri3397.
- Spits, Hergen; Cupedo, Tom (23 April 2012). "Innate Lymphoid Cells: Emerging Insights in Development, Lineage Relationships, and Function". Annual Review of Immunology. 30 (1): 647–675. PMID 22224763. doi:10.1146/annurev-immunol-020711-075053.
- Palm, Noah W.; Rosenstein, Rachel K.; Medzhitov, Ruslan (25 April 2012). "Allergic host defences". Nature. 484 (7395): 465–472. doi:10.1038/nature11047.
- Dadi, Saida; et al. (2016). "Cancer immunosurveillance by tissue-resident innate lymphoid cells and innate-like T cells". Cell. 164 (3): 365–377. doi:10.1016/j.cell.2016.01.002.
- Cerwenka, Adelheid; Lanier, Lewis L. (October 2001). "Natural killer cells, viruses and cancer". Nature Reviews Immunology. 1 (1): 41–49. doi:10.1038/35095564.
- Smyth, Mark J.; Godfrey, Dale I.; Trapani, Joseph A. (1 April 2001). "A fresh look at tumor immunosurveillance and immunotherapy". Nature Immunology. 2 (4): 293–299. PMID 11276199. doi:10.1038/86297.
- Houchins, JP; Yabe, T; McSherry, C; Bach, FH (1991). "DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells". The Journal of Experimental Medicine. 173 (4): 1017–20. PMC . PMID 2007850. doi:10.1084/jem.173.4.1017.
- Fuchs, Anja; et al. (2013). "Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12-and IL-15-responsive IFN-γ-producing cells". Immunity. 38 (4): 769–781. doi:10.1016/j.immuni.2013.02.010.
- Lechner, Melissa G.; Liebertz, Daniel J.; Epstein, Alan L. (2010). "Characterization of cytokine-induced myeloid-derived suppressor cells from normal human peripheral blood mononuclear cells". The Journal of Immunology. 185 (4): 2273–2284. doi:10.4049/jimmunol.1000901.
- Heeren, A. Marijne, et al. "High and interrelated rates of PD-L1+ CD14+ antigen-presenting cells and regulatory T cells mark the microenvironment of metastatic lymph nodes from patients with cervical cancer." Cancer immunology research (2014): canimm-0149.
- Zhu, Jinfang (2015). "T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production". Cytokine. 75 (1): 14–24. doi:10.1016/j.cyto.2015.05.010.
- Ikutani, Masashi; et al. (2012). "Identification of Innate IL-5–Producing Cells and Their Role in Lung Eosinophil Regulation and Antitumor Immunity". The Journal of Immunology. 188 (2): 703–713. doi:10.4049/jimmunol.1101270.
- Wang, K.; Karin, M. (2015). "The IL-23 to IL-17 cascade inflammation-related cancers". Clin Exp Rheumatol. 33 (Suppl 92): S87–S90.
- Oboki, Keisuke; Nakae, Susumu; Matsumoto, Kenji; Saito, Hirohisa (2011). "IL-33 and Airway Inflammation". Allergy, Asthma and Immunology Research. 3 (2): 81. doi:10.4168/aair.2011.3.2.81.
- Kondo, H; Ichikawa, Y; Imokawa, G (March 1998). "Percutaneous sensitization with allergens through barrier-disrupted skin elicits a Th2-dominant cytokine response.". European Journal of Immunology. 28 (3): 769–79. PMID 9541570. doi:10.1002/(SICI)1521-4141(199803)28:03<769::AID-IMMU769>3.0.CO;2-H.
- Vivier, E.; Raulet, D. H.; Moretta, A.; Caligiuri, M. A.; Zitvogel, L.; Lanier, L. L.; Yokoyama, W. M.; Ugolini, S. (6 January 2011). "Innate or Adaptive Immunity? The Example of Natural Killer Cells". Science. 331 (6013): 44–49. doi:10.1126/science.1198687.
- Baxter, Alan G.; Smyth, Mark J. (January 2002). "The Role of NK Cells in Autoimmune Disease". Autoimmunity. 35 (1): 1–14. doi:10.1080/08916930290005864.