T helper 17 cell

T helper 17 cells (Th17) are a subset of T helper cells producing interleukin 17 (IL-17). They are developmentally distinct from Th1 and Th2 cells.

They create inflammation and tissue injury in autoimmune disease[1][2][3] such as multiple sclerosis (which was previously thought to be caused by Th1 cells), psoriasis, autoimmune uveitis, juvenile diabetes, rheumatoid arthritis, and Crohn's disease. Th17 has also been suspected to play a role in allergen-induced airway responses. [4]

Their normal role is to provide 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 lack of Th17 cells leaves the host susceptible to opportunistic infections.

Differentiation

Transforming growth factor beta (TGF-β), interleukin 6 (IL-6), interleukin 21 (IL-21) and interleukin 23 (IL-23) contribute to Th17 formation in mice and humans.[5][6]

It has recently been questioned, however, whether TGF-β is involved at all in humans, and it is assumed that interleukin 1β 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).[5] Effector cytokines associated with this cell type are IL-17, IL-21 and IL-22.[7]

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 a 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.[8] IL-21, a cytokine produced by Th17 cells themselves, has also been shown to initiate an alternative route for the activation of Th17 populations.[9] In humans, a combination of TGF-β, IL-1β and IL-23 induces Th17 differentiation from naive T cells.[6] Both interferon gamma (IFNγ) and IL-4, the main stimulators of Th1 and Th2 differentiation, respectively, have been shown to inhibit Th17 differentiation.

Functions

Th17 cells, particularly auto-specific Th17 cells, are associated with autoimmune disease. The Th17 effector cells are triggered by IL-6 and TGF beta or IL-23 and IL-1beta. Their main effector cytokines are IL-17a, IL-21, and IL-22. The main Th17 effector cells are neutrophils as well as IgM/IgA B cells, and IL-17 CD4 T cells. The key Th17 transcription factors are STAT3 and RORg. The Th17 cells can alter their differentiation program ultimately giving rise to either protective or pro-inflammatory pathogenic cells. The protective and non-pathogenic Th17 cells induced by IL-6 and TGF beta are termed as Treg17 cells. The pathogenic Th17 cells are induced by IL-23 and IL-1 beta.[10] TH17 cells can activate neutrophils to kill extracellular bacteria and fungi. Th17 cells may attack cancers, but this is debated.[11]

The original function of Th17 cells is to protect the body against bacteria and fungi. Though Th17 cells are implicated in anti-fungal immunity, it is thought to be limited to particular sites with detrimental effects observed.[12] Th17 cells produce two main members of the IL-17 family, IL-17A and IL-17F, which cause recruitment, activation and migration of neutrophils. They also secrete IL-21 and IL-22. Th17 cells mediate the regression of tumors in mice.[13][14] Th17 may contribute to the development of late phase asthmatic response due to its increases in gene expression relative to Treg cells. [15]

References

  1. ↑ 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): 139–145. doi:10.1038/nm1551. PMID 17290272.
  2. ↑ 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): 1123–1132. doi:10.1038/ni1254. PMID 16200070.
  3. ↑ Stockinger B, Veldhoen M (June 2007). "Differentiation and function of Th17 T cells". Current Opinion in Immunology 19 (3): 281–286. doi:10.1016/j.coi.2007.04.005. PMID 17433650.
  4. ↑ Naji N., Smith S.G., Gauvreau G.M., O'Byrne P.M. (November 2014). "T Helper 17 Cells and Related Cytokines after Allergen Inhalation Challenge in Allergic Asthmatics". Int Arch Allergy Immunol 165 (1): 27–34. doi:10.1159/000367789. PMID 25301201.
  5. ↑ 5.0 5.1 Dong C (May 2008). "TH17 cells in development: an updated view of their molecular identity and genetic programming". Nature Reviews Immunology 8 (5): 337–348. doi:10.1038/nri2295. PMID 18408735.
  6. ↑ 6.0 6.1 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): 641–649. doi:10.1038/ni.1610. PMC 2597394. PMID 18454151.
  7. ↑ Ouyang W, Kolls JK, Zheng Y (April 2008). "The biological functions of T helper 17 cell effector cytokines in inflammation". Immunity 28 (4): 454–467. doi:10.1016/j.immuni.2008.03.004. PMC 3424508. PMID 18400188.
  8. ↑ 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): 235–238. doi:10.1038/nature04753. PMID 16648838.
  9. ↑ 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): 484–487. doi:10.1038/nature05970. PMID 17581588.
  10. ↑ Singh B, Schwartz JA, Sandrock C, Bellemore SM, Nikoopour E (2013). "Modulation of autoimmune diseases by interleukin (IL)-17 producing regulatory T helper (Th17) cells". Indian J Med Res 138 (5): 591–4. PMID 24434314.
  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): 1016–1022. doi:10.1038/nm.2015. PMC 3034219. PMID 19701202.
  12. ↑ Vautier, S; da Glo´ ria Sousa, M, Brown, G. "C-type lectins, fungi and Th17 responses". Cytokine & Growth Factor Reviews 21 (6): 405–412. doi:10.1016/j.cytogfr.2010.10.001.
  13. ↑ Muranski P; Boni A; Antony PA et al. (July 2008). "Tumor-specific Th17-polarized cells eradicate large established melanoma". Blood 112 (2): 362–373. doi:10.1182/blood-2007-11-120998. PMC 2442746. PMID 18354038.
  14. ↑ 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): 787–798. doi:10.1016/j.immuni.2009.09.014. PMC 2787786. PMID 19879162.
  15. ↑ Singh A, Yamamoto M, Ruan J, Choi JY, Gauvreau GM, Olek S, Hoffmueller U, Carlsten C, FitzGerald JM, Boulet LP, O'Byrne PM, Tebbutt SJ. (24 Jun 2014). "Th17/Treg ratio derived using DNA methylation analysis is associated with the late phase asthmatic response.". Allergy Asthma Clin Immunol 10 (1): 32. doi:10.1186/1710-1492-10-32. PMC 4078401. PMID 24991220.

External links

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