T helper 17 cell

T helper 17 cells (Th17) are a subset of T helper cells producing interleukin 17 (IL-17) discovered in 2007. 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 such as multiple sclerosis (which was previously thought to be caused by Th1 cells), but also psoriasis, autoimmune uveitis, juvenile diabetes, rheumatoid arthritis, and Crohn's disease.

More specifically, they are thought to play a role in inflammation and tissue injury in these conditions. 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.

Differentiation
It remains unclear exactly which cytokines 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. 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). Effector cytokines associated with this cell type are IL-17, IL-21 and IL-22.

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

Functions
On initial characterisation, Th17 cells were broadly implicated in autoimmune disease, and auto-specific Th17 cells were shown to be highly pathologic. A more natural role for Th17 cells is suggested by studies that have demonstrated preferential induction of IL-17 in cases of host infection with various bacterial and fungal species. Th17 cells 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 in mice. Whether the highly inflammatory nature of Th17 cells is sufficient to cause or contribute to carcinogenesis is the subject of current debate.