Th17 ells and Their Role - Essay Example

Introduction The normal immune response is necessary for the efficient control of infectious agents, although if not regulated correctly, it could lead to chronic inflammatory and autoimmune diseases. The CD4 T cell is one of the main components of the normal adaptive immune response. The differentiation of effector CD4 T cells by cytokines occurs due to activation of cells of the innate immune system by various pathogens. Traditionally, two distinct lineages of the effector CD4 T cells have been recognised, which are based on their cytokine production profile: T helper (Th) 1 and the Th2 lineage. The Th1 cells are involved in the destruction of intracellular pathogens (bacteria, viruses and some protozoa). Th1 cells produce interferon (IFN) g, which is a potent activator of cell-mediated immunity. Th2 cells are involved in the destruction of parasitic infections (e.g. helminths). Th2 cells produce interleukins (IL-4, 5, and 13), which are potent activators of B-cell immunoglobulin (Ig) E production, eosinophil recruitment and mucous production and hypermotility. Any immune dysregulation of Th1 responses to self or commensal floral antigens can promote tissue destruction and chronic inflammation, while dysregulation of Th2 responses can lead to allergy and asthma (Harrington, Mangan, Weaver, 2006). Recent studies have suggested a new effector CD4 T-cell arm-called the Th17 (Harrington, Mangan, Weaver, 2006). It has been suggested that the Th17 lineage also must have evolved to control certain classes of pathogens, and aberrant Th17 responses have been implicated in a growing list of autoimmune disorders. Regulatory mechanisms of T cells are important. Redirection or immune deviation of Th1 or Th2-dominated responses is provided by cytokines (IFN-gamma, IL-4) and by chemokines, CXCL4 and CXCL10. Adaptive Treg cells can suppress both Th1 and Th2 responses through contact-dependent mechanisms and/or the production of IL-10 and transforming growth factor-beta (TGF-beta). TGF-beta1 can promote the development of both Th17 effector and adaptive Treg cells, while IL-6 contributes to the development of Th17 cells, but inhibits Treg cells. The development of Th17 cells is also down-regulated by IL-4 produced by Th2 cells and by IFN-gamma produced by Th1 cells (Romagnani S, 2006) Development of Th1, Th2 and Th17 cells Th1 cell development is promoted by the cytokine, interleukin-12 (IL-12). Th1 cells secrete IFN-γ, IL-2 and TNF-β (lymphotoxin), which destroys intracellular pathogens by cell-mediated immunity. Th2 cells are produced when T cells are stimulated in the presence of IL-4. Th2 cells secrete IL-4, IL-5, IL-10 and IL-13, and up-regulate antibody-mediated responses to destroy extracellular pathogens. Regulatory T cells (Tregs) are involved in the inhibition of immune responses to self-antigens, and failure of this inhibition leads to autoimmune disease (Helliwell, C, 2007). There is evidence that the Th17 lineage leading to production of IL-17, is distinct from the Th1 lineage (Harrington, Mangan, Weaver, 2006). Induction of IL-23R is necessary to develop Th17 cells but IL-23 might not be required for Th17 commitment or IL-17 expression. IL-23 signalling might also be important for amplifying and/or stabilizing the Th17 phenotype in chronic inflammation (Harrington, Mangan, Weaver, 2006.) In addition to IL-23, transforming growth factor-beta (TGF-β1) is also important in the development of Th17 cells (Helliwell, C, 2007). TGF-β1 is a critical cytokine involved in Th17 development. TGF-β1 acts by upregulating the expression of IL-23R, which confers responsiveness to IL-23. Interferon-gamma and IL-4 can antagonize the action of TGF-beta on naive T cells, and inhibits Th17 differentiation; this provides a mechanism for divergence of the Th1, Th2 and Th17 lineages (Mangan et al., 2006). When TGF-β1 is combined with IL-6, it inhibits the expression of FoxP3, a gene transcription factor essential for Treg development; this promotes Th17 and suppresses Treg cell development (Helliwell, C, 2007) Role of TH17 in health Similar to the specialized functions of Th1 and Th2 for destruction of intracellular and extracellular pathogens, the Th17 lineage also must have evolved to control certain classes of pathogens. IL-23 and IL-17 are associated with protecting the host against a variety of bacterial infection models like Klebsiella pneumoniae, but the role of the Th17 lineage in dealing with a range of extracellular bacterial pathogens requires further studies (Harrington, Mangan, Weaver, 2006.) Role of TH17 in disease Multiple sclerosis is a classic example of a disease associated with Th1 cells, whereas allergy is due to excessive Th2 cytokine production (Helliwell, C, 2007). As far as TH17 cells are concerned, studies with mice have shown that when the mice over-expressed TGF-β1, they had increased numbers of Th17 cells and autoimmune disease (Helliwell, C, 2007). In the steady state, TGF-β1 will induce FoxP3+ Tregs and maintain self-tolerance, but in the presence of infection or inflammation, IL-6 produced by the innate immune system will suppress Tregs cells and induce pro-inflammatory response by Th17 (Helliwell, C, 2007) (see Appendix, Figure 1). The IL-23/IL-17 axis (see Appendix, Figure 2) also plays an important role in the development of chronic inflammation and host defences against bacterial infection. In chronic inflammatory states, the antigen-stimulated dendritic cells and macrophages produce IL-23, which in turn promotes the development of Th17/ThIL-17 cells (Iwakura & Ishigame, 2006). The Th17/ThIL-17 cells produce IL-17, which enhances T cell priming and triggers potent inflammatory responses by inducing the production of a variety of inflammatory mediators (Iwakura & Ishigame, 2006). IL-23 also acts on dendritic cells and macrophages in an autocrine/paracrine manner to stimulate the generation of proinflammatory cytokines like IL-1, IL-6, and TNF-α. IL-12–stimulated Th1 cells produce IFN-γ and suppress the differentiation of Th17/ThIL-17 cells (Iwakura & Ishigame, 2006). In bacterial infections, activated macrophages and dendritic cells at the site of infection produce IL-23 rapidly. IL-23 in turn activates local resident Th17/ThIL-17 cells and other cells, which produce IL-17, like CD8+ T cells and γδ T cells. The IL-17, which is thus produced, induces the stromal cells to produce G-CSF. This IL-23/IL-17/G-CSF pathway accelerates the recruitment of neutrophils to the infection site and promotes extracellular bacterial clearance (Iwakura & Ishigame, 2006). The production of IL-1, IL-6, and TNF-α is also increased by IL-23. This occurs in an autocrine/paracrine manner (Iwakura & Ishigame, 2006). There is also increasing evidence to suggest that rheumatoid arthritis and multiple sclerosis are primarily IL-17 autoimmune inflammatory-mediated diseases (Furuzawa-Carballeda, Vargas-Rojas, Cabral, 2007). IL-17 is augmented in the sera and/or tissues of patients with contact dermatitis, asthma, and rheumatoid arthritis. It has been demonstrated in mice that IL-17 is involved in the development of autoimmune arthritis and contact, delayed, and airway hypersensitivity. The expression of IL-17 is also augmented in multiple sclerosis (Komiyama et al., 2006) Experimental autoimmune encephalomyelitis (EAE) in mice is characterised by CNS-specific inflammation, demyelination and neuronal degeneration, and mimics many of the clinical and histological characteristics of relapsing-remitting MS. The pro-inflammatory cytokine IL-17 appears to play a minor role in the acute phase of the disease but a significant role in the relapsing phase of the disease (Komiyama et al., 2006). Tregs are known to possess anti-inflammatory properties and can stop the progress of autoimmune diseases as well as prolong the transplant function. It is therefore suggested that a “skewing of responses towards Th17 or Th1 and away from Treg may be responsible for the development and/or progression of AD or acute transplant rejection in humans” (Afzali et al., 2007). Th17 has been identified as an osteoclastogenic Th cell subset that links T cell activation and bone resorption. The interleukin (IL)-23-IL-17 axis is critical for both the onset phase and the bone destruction phase of autoimmune arthritis; thus, Th17 is a powerful therapeutic target for the bone destruction associated with T cell activation (Sato et al., 2006) Some studies also suggest that Th17 may be involved in the pathogenesis of psoriasis (Blauvelt, 2007). According to a new hypothesis, IL-23 produced by activated DCs is a critical initial event in triggering the formation of psoriasis lesions. Il-23, in turn, stimulates the Th17 cells to produce IL-17A, IL-17F, IL-6, TNF-alpha and IL-22. These Th17 cytokines are responsible for the later cellular events, including activation and proliferation of keratinocytes and endothelial cells (Blauvelt, 2007). The early stage of psoriasis development is characterized by the involvement of TGF-β1. TGF-β1 directly stimulates the keratinocytes to produce IL-23 and induces the differentiation of naïve T cells into Th17 cells. It also induces the influx of inflammatory Dcs into evolving psoriatic plaques (Blauvelt, 2007). At present, there is no direct evidence that Th17 cytokines stimulate keratinocytes proliferation. IL-17A, which is elevated in psoriatic skin, can stimulate neutrophil recruitment, ß-defensin 2 production, and ICAM-1 and MHC class I expression on keratinocytes; and these features are characteristic of psoriasis. IL-17A, however, does not appear to stimulate keratinocyte proliferation directly (Blauvelt, 2007). Conclusion A new effector CD4 T-cell arm, called the Th17 has been described recently. Like Th1 and Th2, it is possible that Th17 cells have evolved to provide adaptive immunity against extracellular pathogens. However, more studies are required to further define the exact range of pathogens linked to Th17. The Th17 lineage leading to the production of IL-17, is distinct from the Th1 lineage. Induction of IL-23R is necessary to develop Th17 cells IL-23 signalling might also be important for amplifying and/or stabilizing the Th17 phenotype in chronic inflammation. In addition, transforming growth factor-beta (TGF-β1) is also important in the development of Th17 cells. The IL-23/IL-17 axis plays an important role in the development of chronic inflammation and host defences against bacterial infection. Aberrant Th17 responses have been implicated in a growing list of autoimmune disorders like multiple sclerosis, rheumatoid arthritis and psoriasis. IL-17 appears to play a significant role in the relapsing phase of multiple sclerosis in experimental autoimmune encephalomyelitis (EAE) in mice. The interleukin (IL)-23-IL-17 axis is critical for both the onset phase and the bone destruction phase of autoimmune arthritis. Skewing of responses towards Th17 may be responsible for the development and/or progression of acute transplant rejection in humans. IL-17A, which is elevated in psoriatic skin, can stimulate neutrophil recruitment, ß-defensin 2 production, and ICAM-1 and MHC class I expression on keratinocytes, which are characteristic of psoriasis. References Afzali, B, Lombardi, G, Lechler, RI, Lord, GM (2007). The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol. 148(1):32-46. Blauvelt, A (2007). New concepts in the pathogenesis and treatment of psoriasis: key roles for IL-23, IL-17A and TGF-ß1. ExpertRev.Dermatol. 2(1),69–78(207). Furuzawa-Carballeda, J, Vargas-Rojas, MI, Cabral, AR (2007). Autoimmune inflammation from the Th17 perspective. Autoimmun Rev. 6(3):169-75. Harrington, LE, Mangan, PR, Weaver, CT (2006). Expanding the effector CD4 T-cell repertoire: the Th17 lineage. Current Opinion in Immunology. 18:349–356. Helliwell, C (2007). ACNR. 6 (6). Iwakura, Y, Ishigame, H (2006). The IL-23/IL-17 axis in inflammation. J Clin Invest. 116(5): 1218–1222. Komiyama, Y, Nakae, S, Matsuki, T, Nambu, A, Ishigame, H, Kakuta, S, Sudo, K, Iwakura, Y (2006 ). IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol. 1;177(1):566-73. Mangan, PR, Harrington, LE, OQuinn, DB, Helms, WS, Bullard, DC, Elson, CO, Hatton RD, Wahl, SM, Schoeb, TR, Weaver, CT (2006). Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 11;441(7090):231-4. Romagnani, S (2006). Regulation of the T cell response. Clin Exp Allergy. 36(11):1357-66. Sato, K, Suematsu, A, Okamoto, K, Yamaguchi, A, Morishita, Y, Kadono, Y, Tanaka, S, Kodama, T, Akira, S, Iwakura, Y, Cua, DJ, Takayanagi, H (2006). Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 203(12):2673-82. Appendix Fig 1. (Source-Helliwell, C, 2007. ACNR. ). Fig 2. IL-23/IL-17 axis in inflammation and infection. 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