Type 3 innate lymphoid cells

Type 3 innate lymphoid cells (ILC3) are lymphoid line immune cells and are one of the classified type of Innate lymphoid cells. Due to their functions, they fall into the innate component of the immune system, not adaptive. Participates in innate defence mechanisms on mucous membranes. They are part of a heterogeneous group of cells that are divided into three groups - ILC 1, ILC 2 and ILC 3.[1]

Characterization of ILC 3

ILC 3 consists of two cell types - LTi cells (lymphoid tissue-inducing cells) that are important to produce secondary lymphoid organs in embryogenesis and cells designated as NCR+ ILC 3 and NCR−ILC 3 depending on whether they express NCR receptors of NK cells capable of recognizing pathogenic molecules. They produce cytokines typical for the population of Th17 helper lymphocytes. The characteristic feature of ILC 3 is the expression of the RORγt transcription factor, which is needed for its development and expression of the chemokine receptor CCR6.[1] This group of ILC produces IL-17 (especially IL-17A) [2] and IL-22.[3] Both cytokines can be produced by ILC 3 simultaneously or separately, provided that when IL-22 is produced alone it is a matter of NCR+ ILC 3.[3] ILC 3 express IL-23R and the production of IL-17 and IL-22 is stimulated by IL-23 and IL-1β.[4] For ILC 3, the expression of the transcription factor RORγt and partially also the Ahr (aryl hydrocarbon receptor) is typical since interactions of these two transcription factors cause the accumulation of ILC 3 and the production of IL-22 in the intestines.[5]

Function of ILC 3

ILC 3 represent a defense against extracellular parasites and are involved in maintaining intestinal homeostasis.[6] They participate in effective antimicrobial defence through the production of IL-17 and IL-22. The role of IL-22 in humans and mice is somewhat different. In the murine model, IL-22 was found to play a role in improving the course of inflammatory bowel disease and epithelial restoration in the loss of the protective mucin barrier in the large intestine.[7][8] However, in humans with inflammatory bowel disease, IL-22 has an effect on the pathology of the disease.[9] IL-22 is an important cytokine for maintaining intestinal homeostasis. The action of IL-22 helps enhance the defense of the surface of the intestinal mucosa by weakening the mucin layer [8] and its ability to produce antimicrobial agents, such as β-defensins, is a powerful mechanism that helps maintain intestinal homeostasis.[10] An increase in IL-22 levels together with increased β-defensin expression has been reported in inflammatory skin diseases such as psoriasis. IL-22, as well as IL-17, could thus be involved in the development of these skin diseases, since in humans without these problems IL-22 expression was not registered.[11] The effects of IL-17 and IL-22 can complement each other and stimulate an increased amount of antimicrobial peptides at the site of action.[12] Like ILC2, ILC 3 can express MHC II and be appropriating the function of antigen presenting cells.[13] However, ILCs lack the costimulatory receptors that are necessary for proper activation and initiation of the immune response. ILCs, on the contrary, may set the helper T lymphocytes in the state of anergy. In the case of ILC 3, the ability to express MHC II apparently serves to maintain tolerance to commensal bacteria in the intestine. They suppress the response of CD4 + T lymphocytes to harmless and beneficial intestinal bacteria. If this tolerance is not maintained, there can be a development of undesirable pathological conditions.[13] On the other hand, the action of IL-23 or IL-17 is not always beneficial. It causes some autoimmune diseases such as multiple sclerosis[14] or rheumatoid arthritis.[15] IL-17A specifically targets keratinocytes and is the major cytokine causing pathogenesis of skin psoriasis.[16] In addition, IL-17A is also expressed to an increasing extent in patients with inflammatory bowel disease[17] ILC 3 may play a role already in the prenatal setting of the body's resistance to infections. LTi cells are important in the origin and development of secondary lymphoid organs. It has been found that differentiation and signalling of LTi cells are dependent on retinoic acid (a component of vitamin A). The uptake of retinoic acid in the diet by the mother directly affects the development of LTi cells and the size of the secondary lymphoid organs of the fetus, which may have an effect at its later age[18]

References
  1. Spits, Hergen, et al. "Innate lymphoid cells--a proposal for uniform nomenclature." Nature reviews. Immunology 13.2 (2013): 145
  2. Takatori, Hiroaki, et al. "Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22." Journal of Experimental Medicine 206.1 (2009): 35-41.
  3. Cella, Marina, et al. "A human NK cell subset provides an innate source of IL-22 for mucosal immunity." Nature 457.7230 (2009): 722.
  4. Cella, Marina, Karel Otero, and Marco Colonna. "Expansion of human NK-22 cells with IL-7, IL-2, and IL-1β reveals intrinsic functional plasticity." Proceedings of the National Academy of Sciences 107.24 (2010): 10961-10966.
  5. Qiu, Ju, et al. "The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells." Immunity 36.1 (2012): 92-104.
  6. Spits, Hergen, et al. "Innate lymphoid cells--a proposal for uniform nomenclature." Nature reviews. Immunology 13.2 (2013): 145.
  7. Sugimoto, Ken, et al. "IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis." The Journal of clinical investigation 118.2 (2008): 534.
  8. Sovran, Bruno, et al. "IL-22-STAT3 pathway plays a key role in the maintenance of ileal homeostasis in mice lacking secreted mucus barrier." Inflammatory Bowel Diseases 21.3 (2015): 531-542.
  9. Andoh, Akira, et al. "Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts." Gastroenterology 129.3 (2005): 969-984.
  10. Liang, Spencer C., et al. "Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides." Journal of Experimental Medicine 203.10 (2006): 2271-2279.
  11. Wolk, Kerstin, et al. "IL-22 increases the innate immunity of tissues." Immunity 21.2 (2004): 241-254.
  12. Liang, Spencer C., et al. "Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides." Journal of Experimental Medicine 203.10 (2006): 2271-2279).
  13. Hepworth, Matthew R., et al. "Innate lymphoid cells regulate CD4+ T cell responses to intestinal commensal bacteria." Nature 498.7452 (2013): 113.
  14. Matusevicius, Dea, et al. "Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis." Multiple Sclerosis Journal 5.2 (1999): 101-104.
  15. Ziolkowska, Maria, et al. "High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism." The Journal of Immunology 164.5 (2000): 2832-2838.
  16. Lynde, Charles W., et al. "Interleukin 17A: toward a new understanding of psoriasis pathogenesis." Journal of the American Academy of Dermatology 71.1 (2014): 141-150.
  17. Fujino, S., et al. "Increased expression of interleukin 17 in inflammatory bowel disease." Gut 52.1 (2003): 65-70.
  18. van de Pavert, Serge A., et al. "Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity." Nature 508.7494 (2014): 123.
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