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T helper 17 cells (Th17) are a newly discovered subset of T helper cells producing interleukin 17 (IL-17). They are considered developmentally distinct from Th1 and Th2 cells and excessive amounts of the cell are thought to play a key role in autoimmune disease[1][2] such as Multiple Sclerosis (which was previously thought to be caused by Th1 cells).

More specifically, they are thought to play a role in inflammation and tissue injury in these conditions.[3] Th17 cells can cause severe autoimmune diseases, however they serve a very important function in anti-microbial immunity at epithelial / mucosal barriers. They produce cytokines (such as interleukin 22) which stimulates epithelial cells to produce anti-microbial proteins to clear out certain types of microbe (such as Candida and Staphylococcus). Thus, a severe lack of Th17 cells may leave the host susceptible to opportunistic infections.

Contents

Differentiation

It remains unclear which cytokines exactly contribute to Th17 formation, but transforming growth factor beta (TGF-β), interleukin 6 (IL-6), interleukin 21 (IL-21) and interleukin 23 (IL-23) have been implicated in mice and humans.[4][5] It has recently been questioned, however whether TGF-beta is involved at all in humans, and it is supposed that interleukin 1beta may also play a role. Other proteins involved in their differentiation are signal transducer and activator of transcription 3 (STAT3) and the retinoic-acid-receptor-related orphan receptors alpha (RORα) and gamma (RORγ).[4] Effector cytokines associated with this cell type are IL-17, IL-21 and IL-22.[6]

Activation of precursor T helper cells in the presence of TGF-β and IL-6 is thought to drive differentiation of Th17 cells in the mouse. Aside from cytokine environment, it is unclear whether any other elements of the initial activation of Th17 cells differ from those of other T helper cells. It has been suggested that IL-23 is involved in the expansion of established Th17 populations, but this cytokine alone does not induce differentiation of naive T-cell precursors into this cell type.[7] IL-21, a cytokine produced by Th17 cells themselves, has also been shown to initiate an alternative route for the activation of Th17 populations.[8] In humans, a combination of TGF-β, IL-1β and IL-23 induces Th17 differentiation from naive T cells.[5] Both interferon gamma (IFNγ) and IL-4, the main stimulators of Th1 and Th2 differentiation respectively, have been shown to negatively regulate Th17 differentiation.

Functions

On initial characterisation, Th17 cells were broadly implicated in autoimmune disease and auto-specific Th17 were shown to be highly pathogenic. A more natural role for Th17 cells is suggested by studies which have demonstrated preferential induction of IL-17 in cases of host infection with various bacterial and fungal species. Th17 primarily produce two main members of the IL-17 family; IL-17A and IL-17F which are involved in the recruitment, activation and migration of neutrophils. These cells also secrete IL-21 and IL-22. Recently, Th17 polarized cells have been shown to mediate the regression of established tumors.[9][10] Whether the highly inflammatory nature of Th17 cells is sufficient to cause or contribute to carcinogenesis is the subject of current debate.[11]

References

  1. ^ Harrington LE, Hatton RD, Mangan PR, et al. (November 2005). "Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages". Nature Immunology 6 (11): 1123–32. doi:10.1038/ni1254. PMID 16200070.  
  2. ^ Stockinger B, Veldhoen M (June 2007). "Differentiation and function of Th17 T cells". Current Opinion in Immunology 19 (3): 281–6. doi:10.1016/j.coi.2007.04.005. PMID 17433650.  
  3. ^ Steinman L (February 2007). "A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage". Nat. Med. 13 (2): 139–45. doi:10.1038/nm1551. PMID 17290272.  
  4. ^ a b Dong C (May 2008). "TH17 cells in development: an updated view of their molecular identity and genetic programming". Nature Reviews Immunology 8 (5): 337–48. doi:10.1038/nri2295. PMID 18408735.  
  5. ^ a b Manel N, Unutmaz D, Littman DR (June 2008). "The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat". Nature Immunology 9 (6): 641–9. doi:10.1038/ni.1610. PMID 18454151.  
  6. ^ Ouyang W, Kolls JK, Zheng Y (April 2008). "The biological functions of T helper 17 cell effector cytokines in inflammation". Immunity 28 (4): 454–67. doi:10.1016/j.immuni.2008.03.004. PMID 18400188.  
  7. ^ Bettelli E, Carrier Y, Gao W, et al. (May 2006). "Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells". Nature 441 (7090): 235–8. doi:10.1038/nature04753. PMID 16648838.  
  8. ^ Korn T, Bettelli E, Gao W, et al. (July 2007). "IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells". Nature 448 (7152): 484–7. doi:10.1038/nature05970. PMID 17581588.  
  9. ^ Muranski P, Boni A, Antony PA, et al. (July 2008). "Tumor-specific Th17-polarized cells eradicate large established melanoma". Blood 112 (2): 362–73. doi:10.1182/blood-2007-11-120998. PMID 18354038.  
  10. ^ Martin-Orozco N, Muranski P, Chung Y, et al. (November 2009). "T helper 17 cells promote cytotoxic T cell activation in tumor immunity". Immunity 31 (5): 787–98. doi:10.1016/j.immuni.2009.09.014. PMID 19879162.  
  11. ^ Wu S, Rhee KJ, Albesiano E, et al. (September 2009). "A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses". Nature Medicine 15 (9): 1016–22. doi:10.1038/nm.2015. PMID 19701202.  

External links

There are some open access Network Protocols for studying Th17 cells at Nature Protocols:

  • Egwuagu (2007). "TH17 cells contribute to uveitis and scleritis and are inhibited by IL-27/STAT1 in the retina (3) Western Blot Analysis". Nature Protocols. doi:10.1038/nprot.2007.382.  
  • Egwuagu (2007). "TH17 cells contribute to uveitis and scleritis and are inhibited by IL-27/STAT1 in the retina (4) Confocal microscopy". Nature Protocols. doi:10.1038/nprot.2007.383.  
  • Egwuagu (2007). "TH17 cells contribute to uveitis and scleritis and are inhibited by IL-27/STAT1 in the retina (5) Chromatin immunoprecipitation". Nature Protocols. doi:10.1038/nprot.2007.384.  
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